GIP/GLP1 co-agonist compounds

ABSTRACT

The present invention relates to compounds having activity at both the human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. The present invention also relates to compounds having an extended duration of action at each of these receptors. Furthermore, the present invention relates to compounds that may be administered orally. Compounds may be useful in the treatment of type 2 diabetes mellitus (“T2DM”). Also, the compounds may be useful in the treatment of obesity.

The present invention relates to compounds having activity at both thehuman glucose-dependent insulinotropic polypeptide (GIP) andglucagon-like peptide-1 (GLP-1) receptors. The present invention alsorelates to compounds having an extended duration of action at each ofthese receptors. Furthermore, the present invention relates to compoundsthat may be administered orally. Compounds may be useful in thetreatment of type 2 diabetes mellitus (“T2DM”). Also, the compounds maybe useful in the treatment of obesity.

Over the past several decades, the prevalence of diabetes has continuedto rise. T2DM is the most common form of diabetes accounting forapproximately 90% of all diabetes. T2DM is characterized by high bloodglucose levels associated mainly with insulin resistance. The currentstandard of care for T2DM includes diet and exercise, treatment withoral medications, and injectable glucose lowering drugs, includingincretin-based therapies, such as GLP-1 receptor agonists. A variety ofGLP-1 receptor agonists are currently available for treatment of T2DM,although currently marketed GLP-1 receptor agonists are generallydose-limited by gastrointestinal side effects such as nausea andvomiting. Subcutaneous injection is the typical route of administrationfor the available GLP-1 receptor agonists. When treatment with oralmedications and incretin-based therapies are insufficient, insulintreatment is considered. Despite the advances in treatment availabletoday, many patients with T2DM are unable to reach their glycemiccontrol goals. Uncontrolled diabetes leads to several conditionsassociated with increased morbidity and mortality of patients. There isa need for a treatment to enable more patients with T2DM to reach theirglycemic treatment goal.

Obesity is a complex medical disorder resulting in excessiveaccumulation of adipose tissue mass. Today obesity is a global publichealth concern that is associated with undesired health outcomes andmorbidities. Desired treatments for patients with obesity strive toreduce excess body weight, improve obesity-related co-morbidities, andmaintain long-term weight reduction. Available treatments for obesityare particularly unsatisfactory for patients with severe obesity. Thereis a need for alternative treatment options to induce therapeutic weightloss in patients in need of such treatment.

WO2016/111971 describes peptides stated to have GLP-1 and GIP activity.WO2013/164483 also discloses compounds stated to have GLP-1 and GIPactivity.

There is a need for T2DM treatments capable of providing effectiveglucose control for a larger portion of the patients in need of suchtreatment. There is a further need for T2D treatments capable ofproviding effective glucose control and with a favorable side effectprofile. There is a need for alternate treatment options to providetherapeutic weight loss in a patient in need of such treatment. There isa need for an alternate treatment option for a patient in need oftreatment for severe obesity.

There is a desire for compounds having agonist activity at the GIP andGLP-1 receptors that are suitable for oral administration. Compoundswith extended duration of action at each of the GIP and GLP-1 receptorsare desirable to allow for less frequent dosing of the compound.

Accordingly, the present invention provides a compound of Formula I:

(SEQ ID NO: 3) R₁X₁X₂X₃GTX₆TSDX₁₀X₁₁X₁₂X₁₃X₁₄DX₁₆X₁₇AX₁₉X₂₀X₂₁X₂₂X₂₃X₂₄X₂₅X₂₆X₂₇X₂₈X₂₉X₃₀X₃₁

-   -   wherein:    -   R₁ is a modification of the N-terminal amino group wherein the        modification is selected from the group consisting of Ac and        absent;    -   X₁ is selected from the group consisting of Y, H, D-Tyr, F,        desH, and desY,    -   X₂ is selected from the group consisting of Aib, αMeP, A, P, and        D-Ala;    -   or X₁ and X₂ combine to form desH-ψ[NHCO]-Aib;    -   X₃ is selected from the group consisting of E, N, Aad, and cTA;    -   X₆ is selected from the group consisting of F, αMeF, and        αMeF(2F);    -   X₁₀ is selected from the group consisting of A, L, H, 3Pal,        4Pal, V, Y, E, αMeF, αMeF(2F), I, αMeY, Q, D-His, D-Tyr, cTA,        and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₁₁ is selected from the group consisting of S, αMeS, and D-Ser;    -   X₁₂ is selected from the group consisting of I, S, D-Ile, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₁₃ is selected from the group consisting of Nle, Aib, L, αMeL,        and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₁₄ is selected from the group consisting of L and K, wherein K        is conjugated to a C₁₆-C₂₂ fatty acid wherein said fatty acid is        optionally conjugated to said K via a linker;    -   X₁₆ is selected from the group consisting of K, E, Orn, Dab,        Dap, S, T, H, Aib, αMeK, R, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₁₇ is selected from the group consisting of K, Q, I, and an        amino acid conjugated to a C₁₆-C₂₂ fatty acid wherein said fatty        acid is optionally conjugated to said amino acid via a linker;    -   X₁₉ is selected from the group consisting of Q, A, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₀ is selected from the group consisting of Aib, Q, H, R, K,        αMeK, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₁ is selected from the group consisting of H, Aad, D, Aib, T,        A, E, I, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₂ is selected from the group consisting of F and αMeF;    -   X₂₃ is selected from the group consisting of I, L, A, G, F, H,        E, V, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₄ is selected from the group consisting of S, Aad, D-Glu, E,        Aib, H, V, A, Q, D, P, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₅ is selected from the group consisting of Y and αMeY;    -   X₂₆ is selected from the group consisting of L, αMeL, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₇ is selected from the group consisting of L, I, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₈ is selected from the group consisting of E, A, S, D-Glu, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₉ is selected from the group consisting of Aib, G, A, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₃₀ is selected from the group consisting of C, G, G-R₂ and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H;    -   X₃₁ is absent or is selected from the group consisting of        PX₃₂X₃₃X₃₄—R₂ (SEQ ID NO:4), PX₃₂X₃₃X₃₄X₃₃X₃₆X₃₇X₃₈X₃₉—R₂ (SEQ        ID NO: 5),    -   PX₃₂X₃₃X₃₄X₃₃X₃₆X₃₇X₃₈X₃₉X₄₀—R₂ (SEQ ID NO:6),        K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H]        X₃₂X₃₃X₃₄—R₂ (SEQ ID NO: 7),        K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H]    -   X₃₂X₃₃X₃₄X₃₃X₃₆X₃₇X₃₈X₃₉—R₂ (SEQ ID NO: 8), and        K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H]        X₃₂X₃₃X₃₄X₃₃X₃₆X₃₇X₃₈X₃₉X₄₀—R₂ (SEQ ID NO: 9);        -   wherein:        -   X₃₂ is S or            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₃₃ is S or            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₃₄ is selected from the group consisting of G, C, and            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₃₅ is A or            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₃₆ is P or            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₃₇ is P or            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₃₈ is P or            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₃₉ is selected from the group consisting of C, S, and            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];        -   X₄₀ is selected from the group consisting of C and            K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)_(q)—CO₂H];    -   q is selected from the group consisting of 14, 15, 16, 17, 18,        19, and 20; and    -   R₂ is a modification of the C-terminal group, wherein the        modification is NH₂ or absent;    -   or a pharmaceutically acceptable salt thereof;    -   wherein if X₃₀ is G-R₂, then X₃₁ is absent;    -   wherein no more than one of X₁₀, X₁₂, X₁₃, X₁₄, X₁₆, X₁₇, X₁₉,        X₂₀, X₂₁, X₂₃, X₂₄, X₂₆, X₂₇, X₂₈, X₂₉, X₃₀, X₃₁, X₃₂, X₃₃, X₃₄,        X₃₅, X₃₆, X₃₇, X₃₈, X₃₉, and X₄₀ may be a substituent that        contains a fatty acid; and    -   wherein no more than one of X₃₀, X₃₄, X₃₉, and X₄₀ may be C; and    -   wherein if one of X₃₀, X₃₄, X₃₉, and X₄₀ is C, then none of X₁₀,        X₁₂, X₁₃, X₁₄, X₁₆, X₁₇, X₁₉, X₂₀, X₂₁, X₂₃, X₂₄, X₂₆, X₂₇, X₂₈,        X₂₉, X₃₀, X₃₁, X₃₂, X₃₃, X₃₄, X₃₅, X₃₆, X₃₇, X₃₈, X₃₉, and X₄₀        is a substituent that contains a fatty acid.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein q is 16. In an embodiment is a compoundof Formula I, or a pharmaceutically acceptable salt thereof, wherein X₃₁is selected from the group consisting of SEQ ID NO:5 and SEQ ID NO:8. Inan embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein the X₁₇ amino acid that is conjugatedto a fatty acid is a natural amino acid. In an embodiment is a compoundof Formula I, or a pharmaceutically acceptable salt thereof, wherein X₁₇is selected from the group consisting of K, Q and I.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein K is conjugated to a C₁₆-C₂₂ fatty acidwherein said fatty acid is optionally conjugated to said K via a linker.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X₁₄ or X₁₇ is selected from the groupconsisting ofK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₄—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(Trx)-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(Trx)-(γ-Glu)-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-et)-ethoxy]-acetyl)-(εK)-(γ-Glu)-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(εK)—CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)₂-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)—CO—(CH₂)₁₆—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)—CO—(CH₂)₁₄—CO₂H, andKDab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Dab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO—(CH₂)₁₈—CO₂H.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X₁₄ or X₁₇ is selected from the groupconsisting ofK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₄—CO₂H, andK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₈—CO₂H.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X₁₄ or X₁₇ is selected from the groupconsisting ofK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H, andK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₄—CO₂H. In anembodiment is a compound of Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁₄ or X₁₇ is selected from the group consistingof K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H andK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₆—CO₂H. In anembodiment is a compound of Formula I, or pharmaceutically acceptablesalt thereof, wherein X₁₄ or X₁₇ isK(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b)-CO—(CH₂)_(q)—CO₂H,wherein a is 2, b is 1, and q is selected from the group consisting of18 and 20. In an embodiment is a compound of Formula I, orpharmaceutically acceptable salt thereof, wherein X₁₄ or X₁₇ isK(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b)-CO—(CH₂)_(q)—CO₂H,wherein a is 2, b is 1 and q is 18. In an embodiment is a compound ofFormula I, or pharmaceutically acceptable salt thereof, wherein X₁₄ orX₁₇ isK(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b)-CO—(CH₂)_(q)—CO₂H,wherein, a is 2, b is 1, and q is 20.

In an embodiment is a Formula I compound, or pharmaceutically acceptablesalt thereof, wherein X₁ and X₂ do not combine to form desH-ψ[NHCO]-Aib(hereafter a “Formula II” compound).

In an embodiment is a compound of Formula I, or pharmaceuticallyacceptable salt thereof, wherein:

-   -   X₁₇ is an amino acid conjugated to a C₁₆-C₂₂ fatty acid wherein        said fatty acid is optionally conjugated to said amino acid via        a linker; and    -   X₃₀ is selected from the group consisting of G-R₂ and G;    -   wherein if X₃₀ is G, then X₃₁ is selected from the group        consisting of PX₃₂X₃₃X₃₄—R₂ (SEQ ID NO:4), wherein X₃₂ is S, X₃₃        is S and X₃₄ is G (SEQ ID NO:297), and        PX₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₉X₃₉—R₂ (SEQ ID NO:5), wherein X₃₂ is S,        X₃₃ is S, X₃₄ is G, X₃₅ is A, X₃₆ is P, X₃₇ is P, X₃₈ is P and        X₃₉ is S (SEQ ID NO:298) (hereafter a “Formula III” compound).

In an embodiment is a compound of Formula III, or a pharmaceuticallyacceptable salt thereof, wherein the X₁₇ amino acid is conjugated to thefatty acid via a linker (hereafter a “Formula IIIa” compound).

In an embodiment is a compound of Formula III and IIIa, or apharmaceutically acceptable salt thereof, wherein:

-   -   X₁₀ is selected from the group consisting of A, L, H, 3Pal,        4Pal, V, Y, E, αMeF, αMeF(2F), I, αMeY, Q, D-His, D-Tyr, and        cTA;    -   X₁₂ is selected from the group consisting of I, S, and D-Ile;    -   X₁₃ is selected from the group consisting of Nle, Aib, L, and        αMeL;    -   X₁₄ is selected from the group consisting of L and K;    -   X₁₆ is selected from the group consisting of K, E, Orn, Dab,        Dap, S, T, H, Aib, αMeK, and R;    -   X₁₉ is selected from the group consisting of Q, and A;    -   X₂₀ is selected from the group consisting of Aib, Q, H, R, K,        and αMeK;    -   X₂₁ is selected from the group consisting of H, Aad, D, Aib, T,        A, E, and I;    -   X₂₃ is selected from the group consisting of I, L, A, G, F, H,        E, and V;    -   X₂₄ is selected from the group consisting of S, Aad, D-Glu, E,        Aib, H, V, A, Q, D, and P;    -   X₂₆ is selected from the group consisting of L, and αMeL;    -   X₂₇ is selected from the group consisting of L, and I;    -   X₂₈ is selected from the group consisting of E, A, S, and D-Glu;    -   X₂₉ is selected from the group consisting of Aib, G, and A;    -   X₃₀ is selected from the group consisting of G and G-R₂;    -   wherein if X₃₀ is G; then X₃₁ is selected from the group        consisting of PX₃₂X₃₃X₃₄—R₂ (SEQ ID NO:4), wherein X₃₂ is S, X₃₃        is S and X₃₄ is G (SEQ ID NO:297) and        PX₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₉X₃₉—R₂ (SEQ ID NO:5), wherein X₃₂ is S,        X₃₃ is S, X₃₄ is G, X₃₅ is A, X₃₆ is P, X₃₇ is P, X₃₈ is P and        X₃₉ is S (SEQ ID NO:298) (hereafter a “Formula IIIb” compound).

In an embodiment, is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein the linker comprisesfrom 1 to 2 amino acids, and in a further embodiment of these particularFormula III, IIIa and IIIb compounds are those wherein the linker aminoacids are independently selected from the group consisting of Glu andγ-Glu. In another embodiment is a compound of Formula III, IIIa andIIIb, or a pharmaceutically acceptable salt thereof, wherein the linkercomprises from one or two (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)moieties and in a further embodiment of these particular formula III,IIIa and IIIb compounds are those where the linker is(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b), wherein a isselected from the group consisting of 1 or 2; and b is selected from thegroup consisting of 1 or 2.

In an embodiment is a compound of Formula III, or a pharmaceuticallyacceptable salt thereof, wherein X₁₇ is an amino acid conjugated to aC₁₆-C₂₂ fatty acid, wherein the amino acid is K and wherein said fattyacid is optionally conjugated to said amino acid via a linker.

In an embodiment is a compound of Formula III, or pharmaceuticallyacceptable salt thereof, wherein:

-   -   R₁ is absent;    -   X₁ and X₂ do not combine to form desH-ψ[NHCO]-Aib;    -   X₁₇ is K conjugated to a C₁₆-C₂₂ fatty acid wherein said fatty        acid is optionally conjugated to said amino acid via a linker.

In an embodiment is a compound of Formula III, or pharmaceuticallyacceptable salt thereof, wherein:

-   -   X₁ is Y;    -   X₂ is Aib;    -   X₃ is E;    -   X₁₀ is selected from the group consisting of A, L, H, 3Pal,        4Pal, V, and Y;    -   X₁₁ is S;    -   X₁₂ is I;    -   X₁₄ is L;    -   X₁₆ is selected from the group consisting of K, E, Orn, Dab, and        Dap;    -   X₁₇ is K conjugated to a C₁₆-C₂₂ fatty acid wherein said fatty        acid is optionally conjugated to said amino acid via a linker;    -   X₁₉ is Q;    -   X₂₀ is Aib;    -   X₂₁ is selected from the group consisting of H, Aad, D, Aib, T,        A, and E;    -   X₂₂ is F;    -   X₂₃ is I,    -   X₂₄ is selected from the group consisting of S, Aad, D-Glu, and        E;    -   X₂₆ is L; and    -   X₂₅ is selected from the group consisting of E and A.

In an embodiment is a compound of Formula III, or pharmaceuticallyacceptable salt thereof, wherein:

-   -   X₁ is Y;    -   X₂ is Aib;    -   X₃ is E;    -   X₆ is αMeF(2F);    -   X₁₀ is selected from the group consisting of Y, 4-Pal, and V;    -   X₁₁ is S;    -   X₁₂ is I;    -   X₁₃ is selected from the group consisting of L, Aib, and αMeL;    -   X₁₄ is L;    -   X₁₆ is selected from the group consisting of E, K, and Orn;    -   X₁₇ is K conjugated to a C₁₆-C₂₂ fatty acid wherein said fatty        acid is optionally conjugated to said amino acid via a linker;    -   X₁₉ is Q;    -   X₂₀ is Aib    -   X₂₁ is selected from the group consisting of E, A, and T;    -   X₂₂ is F;    -   X₂₃ is I;    -   X₂₄ is D-Glu;    -   X₂₅ is selected from the group consisting of Y and αMeY;    -   X₂₆ is L;    -   X₂₇ is I;    -   X₂₈ is E;    -   X₂₉ is G;    -   X₃₀ is G; and    -   X₃₁ is PX₃₂X₃₃X₃₄X₃₈X₃₆X₃₇X₃₈X₃₉—R₂ (SEQ ID NO:5), wherein X₃₂        is S, X₃₃ is S,    -   X₃₄ is G, X₃₅ is A, X₃₆ is P, X₃₇ is P, X₃₈ is P, X₃₉ is S (SEQ        ID NO:298).

In an embodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein R₂ is absent.

In an embodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein R₂ is NH₂.

In an embodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein X₁₃ is αMeL.

In an embodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein X₂₅ is Y and X₁₃ isαMeL.

In an embodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein X₁₇ is K conjugated toa fatty acid via a linker to the epsilon-amino group of the K side-chainwherein said fatty acid and linker have the following formula:

(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b)-CO—(CH₂)_(q)—CO₂H,wherein a is 1 or 2; b is 1 or 2; and q is selected from the groupconsisting of 14 to 20.

In an embodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein X₁₆ is Orn, X₁₃ isαMeL, and X₂, is Y. In an embodiment is a compound of Formula III, IIIaand IIIb, or a pharmaceutically acceptable salt thereof, wherein X₁₆ isE, X₁₃ is αMeL, and X₂₅ is Y. In an embodiment, is a compound of FormulaIII, IIIa and IIIb, or a pharmaceutically acceptable salt thereof,wherein X₁₆ is E, X₁₃ is αMeL, X₁₀ is Y, and X₂₅ is αMeY. In anembodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein X₁₆ is Orn, X₁₃ isαMeL, X₁₀ is 4Pal, and X₂₅ is Y. In an embodiment is a compound ofFormula III, IIIa and IIIb, or a pharmaceutically acceptable saltthereof, wherein X₁₆ is Orn, X₁₃ is αMeL, X₁₀ is V, and X₂₅ is Y. In anembodiment is a compound of Formula III, IIIa and IIIb, or apharmaceutically acceptable salt thereof, wherein X₁₆ is E, X₁₃ is αMeL,X₂₅ is Y, and X₁₇ isK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b)-CO—(CH₂)_(q)—CO₂H,wherein a is 2; b is 1; and q is selected from the group consisting of14 to 20. In an embodiment is a compound of Formula III, IIIa and IIIb,or a pharmaceutically acceptable salt thereof, wherein X₁₆ is E, X₁₃ isαMeL, X₁₀ is Y, and X₂₅ is Y and and X₁₇ isK(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b)-CO—(CH₂)_(q)—CO₂H,wherein a is 2; b is 1; and q is selected from the group consisting of16 to 20.

In an embodiment is a compound of Formula I selected from the groupconsisting of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13,and SEQ ID NO:14, or a pharmaceutically acceptable salt thereof. In anembodiment is a compound of Formula I that is SEQ ID NO:10, or apharmaceutically acceptable salt thereof. In an embodiment is a compoundof Formula I that is SEQ ID NO: 11, or a pharmaceutically acceptablesalt thereof. In an embodiment is a compound of Formula I that is SEQ IDNO: 12, or a pharmaceutically acceptable salt thereof. In an embodimentis a compound of Formula I that is SEQ ID NO: 13, or a pharmaceuticallyacceptable salt thereof. In an embodiment is a compound of Formula Ithat is SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X₁ is selected from the groupconsisting of Y, F, and D-Tyr; X₆ is F; and X₁₃ is selected from thegroup consisting of Aib, L, and αMeL.

In an embodiment, is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein R₁ is absent; X₁ is selected from thegroup consisting of Y, F, and D-Tyr; X₆ is F; X₁₃ is selected from thegroup consisting of Aib, L, and αMeL; X₂ is Aib; X₃ is E; X₁₀ is Y; X₁₁is S; X₁₂ is I; X₁₄ is L; X₁₆ is selected from the group consisting ofK, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R; X₁₇ is an amino acidconjugated to a C₁₆-C₂₂ fatty acid wherein said fatty acid is optionallyconjugated to said amino acid via a linker; X₁₉ is Q; X₂₀ is selectedfrom the group consisting of Aib, Q, H, and K; X₂₁ is selected from thegroup consisting of H, D, T, A, and E; X₂₂ is F; X₂₃ is I; X₂₄ isselected from the group consisting of D-Glu and E; X₂₆ is L; X₂₇ is I;X₂₈ is selected from the group consisting of E, A, S, and D-Glu; X₂₉ isselected from the group consisting of Aib, G, and A; X₃₀ is selectedfrom the group consisting of C, G, and G-R₂; X₃₁ is absent or isselected from the group consisting of PX₃₂X₃₃X₃₄—R₂ (SEQ ID NO:4),PX₃₂X₃₃X₃₄X₃₅X₃X₃₇X₃₉X₃₉—R₂ (SEQ ID NO:5), andPX₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₅X₃₉X₄₀—R₂ (SEQ ID NO:6); wherein: X₃₂ is S; X₃₃ isS; X₃₄ is selected from the group consisting of G and C; X₃₅ is A; X₃₆is P; X₃₇ is P; X₃₈ is P; X₃₉ is selected from the group consisting of Cand S; and X₄₀ is C.

In an embodiment, is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X₁ is selected from the groupconsisting of Y, F, and D-Tyr; X₆ is F; and X₁₃ is selected from thegroup consisting of Aib, L, and αMeL; X₂₅ is A; X₂₉ G; X₃₀ is G; X₃₁ isPX₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₈X₃₉—R₂ (SEQ ID NO:5); X₃₄ is G; and X₃₉ is S.

In an embodiment, is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X₁ is selected from the groupconsisting of Y and D-Tyr; and X₁₃ αMeL.

In an embodiment is a compound of Formula I selected from the groupconsisting of SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:305, SEQ IDNO:306, SEQ ID NO:307, and SEQ ID NO:308, or a pharmaceuticallyacceptable salt thereof. In an embodiment is a compound of Formula Ithat is SEQ ID NO:303, or a pharmaceutically acceptable salt thereof. Inan embodiment is a compound of Formula I that is SEQ ID NO:304, or apharmaceutically acceptable salt thereof. In an embodiment is a compoundof Formula I that is SEQ ID NO:305, or a pharmaceutically acceptablesalt thereof. In an embodiment is a compound of Formula I that is SEQ IDNO:306, or a pharmaceutically acceptable salt thereof. In an embodimentis a compound of Formula I that is SEQ ID NO:307, or a pharmaceuticallyacceptable salt thereof. In an embodiment is a compound of Formula Ithat is SEQ ID NO:308, or a pharmaceutically acceptable salt thereof. Inan embodiment is a compound of Formula I that is SEQ ID NO:386, or apharmaceutically acceptable salt thereof.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X₁₀ is selected from the group consisting of A, L, H, 3Pal,        4Pal, V, Y, αMeF, αMeF(2F), I, αMeY, Q, D-His, E, cTA, and        D-Tyr;    -   X₁₂ is selected from the group consisting of I, D-Ile, and S;    -   X₁₃ is selected from the group consisting of Nle, Aib, L, and        αMeL;    -   X₁₄ is L;    -   X₁₆ is selected from the group consisting of K, E, Orn, Dab,        Dap, S, T, H, Aib, αMeK, and R;    -   X₁₇ is selected from the group consisting of K, Q, and I;    -   X₁₉ is selected from the group consisting of Q and A;    -   X₂₀ is selected from the group consisting of Aib, Q, H, R, K,        and αMeK;    -   X₂₁ is selected from the group consisting of H, Aad, D, Aib, T,        A, E, and I;    -   X₂₃ is selected from the group consisting of I, L, A, G, F, H,        E, and V;    -   X₂₄ is selected from the group consisting of S, Aad, D-Glu, E,        Aib, H, V, A, Q, D, and P;    -   X₂₆ is selected from the group consisting of L and αMeL;    -   X₂₇ is selected from the group consisting of L and I;    -   X₂₈ is selected from the group consisting of E, A, S, and D-Glu;        and    -   X₂₉ is selected from the group consisting of Aib, G, and A        (hereafter a “Formula IV” compound).

In an embodiment of is a compound of Formula IV, or a pharmaceuticallyacceptable salt thereof wherein X₃₉ is C. In an embodiment is a compoundof Formula IV, or a pharmaceutically acceptable salt thereof wherein X₄₀is C.

In an embodiment is a compound of Formula IV, or a pharmaceuticallyacceptable salt thereof, wherein one, and only one, of X₃₀, X₃₄, X₃₉,and X₄₀ is C. In an embodiment is a compound of Formula IV, or apharmaceutically acceptable salt thereof, wherein one, and only one, ofX₃₀, X₃₄, X₃₉, and X₄₀ is C modified using time-extension technology. Inan embodiment is a compound of Formula IV, or pharmaceuticallyacceptable salt thereof, wherein C is modified using time-extensiontechnology wherein the time-extension technology is XTEN. In anembodiment is a compound of Formula IV, or pharmaceutically acceptablesalt thereof, wherein C is modified using time-extension technologywherein the time-extension technology is a (Glu)_(m) biotin wherein m is0, 1, 2, or 3. In an embodiment is a compound of Formula IV, or apharmaceutically acceptable salt thereof, wherein:

-   -   X₁ is Y;    -   X₂ is Aib;    -   X₃ is E;    -   X₁₀ is selected from the group consisting of A, L, H, 3Pal,        4Pal, V, and Y;    -   X₁₁ is S;    -   X₁₂ is I;    -   X₁₆ is selected from the group consisting of K, E, Orn, Dab, and        Dap;    -   X₉ is Q;    -   X₂₀ is selected from the group consisting of Aib and K;    -   X₂₁ is selected from the group consisting of H, Aad, D, Aib, T,        A, and E;    -   X₂₂ is F;    -   X₂₃ is I;    -   X₂₄ is selected from the group consisting of S, Aad, D-Glu, and        E;    -   X₂₆ is L; and    -   X₂₈ is selected from the group consisting of E and A;    -   or a pharmaceutically acceptable salt thereof.

In an embodiment is a compound of Formula IV, or a pharmaceuticallyacceptable salt thereof, wherein

-   -   X₁ is Y;    -   X₂ is Aib;    -   X₃ is E;    -   X₁₀ is selected from the group consisting of A, L, H, 3Pal,        4Pal, V, and Y;    -   X₁₁ is S;    -   X₁₂ is I;    -   X₁₆ is selected from the group consisting of K, E, Orn, Dab, and        Dap;    -   X₂₀ is Aib;    -   X₂₁ is selected from the group consisting of H, Aad, D, Aib, T,        A, and E;    -   X₂₂ is F;    -   X₂₄ is selected from the group consisting of S, Aad, D-Glu, and        E;    -   X₂₇ is I; and    -   X₂₈ is selected from the group consisting of E and A.

In an embodiment is a compound of Formula I, or a pharmaceutical saltthereof, wherein:

-   -   X₁₄ is L;    -   X₁₇ is selected from the group consisting of K, Q, and I;    -   X₃₀ is selected from the group consisting of G-R₂ and G; and    -   q is selected from the group consisting of 16, 18, and 20;    -   wherein if X₃₀ is G, then X₃₁ is selected from the group        consisting of:    -   PX₃₂X₃₃X₃₄—R₂ (SEQ ID NO:4), wherein:        -   X₃₂ is S, X₃₃ is S, X₃₄ is G and R₂ is absent (SEQ ID            NO:299) or        -   X₃₂ is S, X₃₃ is S, X₃₄ is G and R₂ is NH₂ (SEQ ID NO:300);            and    -   PX₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₈X₃₉—R₂ (SEQ ID NO:5), wherein:        -   X₃₂ is S, X₃₃ is S, X₃₄ is G, X₃₅ is A, X₃₆ is P, X₃₇ is P,            X₃₈ is P, X₃₉ is S and        -   R₂ is absent (SEQ ID NO:301) or        -   X₃₂ is S, X₃₃ is S, X₃₄ is G, X₃₅ is A, X₃₆ is P, X₃₇ is P,            X₃₈ is P, X₃₉ is S and        -   R₂ is NH₂ (SEQ ID NO:302); and    -   wherein one of X₁₀, X₁₂, X₁₃, X₁₄, X₁₆, X₁₉, X₂₀, X₂₁, X₂₃, X₂₄,        X₂₆, X₂₇, X₂₈, and X₂₉ is        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-yGlu-CO—(CH₂)qCO₂H        (hereafter a “Formula V” compound).

In an embodiment is a compound of Formula V, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X₁ is Y;    -   X₂ is Aib;    -   X₃ is E;    -   X₁₀ is selected from the group consisting of A, L, H, 3Pal,        4Pal, V, Y, E, cTA, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₁₁ is S;    -   X₁₂ is selected from the group consisting of I, D-Ile, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₁₆ is selected from the group consisting of K, E, Orn, Dab,        Dap, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₁₇ is selected from the group consisting of K and I;    -   X₁₉ is selected from the group consisting of Q and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₀ is selected from the group consisting of Aib and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₁ is selected from the group consisting of H, Aad, D, Aib, T,        A, E, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₂ is F;    -   X₂₄ is selected from the group consisting of S, Aad, D-Glu, E,        and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₆ is selected from the group consisting of L and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H;    -   X₂₇ is selected from the group consisting of L and I; and    -   X₂₈ is selected from the group consisting of E, A, and        K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H.

In an embodiment is a compound of Formula V, or a pharmaceuticallyacceptable salt thereof, wherein X₂₀ isK(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)qCO₂H, whereinq is 16 or 18. In an embodiment is a compound of Formula V, or apharmaceutically acceptable salt thereof, wherein X₃₁ is SEQ ID NO:301or SEQ ID NO:302.

An embodiment provides a method of treating a condition selected fromthe group consisting of T2DM, obesity, nonalcoholic fatty liver disease(NAFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia and metabolicsyndrome, comprising administering to a subject in need thereof, aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof. An embodiment provides a method for providingtherapeutic weight loss comprising administering to a subject in needthereof, an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof. In one embodiment, thecondition is NAFLD. In one embodiment, the condition is NASH.

An embodiment provides a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, for use in therapy. An embodiment provides acompound of Formula I, or a pharmaceutically acceptable salt thereof,for use in therapy to treat a condition selected from the groupconsisting of T2DM, obesity, NAFLD, NASH, dyslipidemia and metabolicsyndrome. In an embodiment, the condition is T2DM. In an embodiment, thecondition is obesity. In an embodiment, the condition is NAFLD. In anembodiment, the condition is NASH. In an embodiment, the condition ismetabolic syndrome.

The compounds of Formula I, or a pharmaceutically acceptable saltthereof, may be useful in the treatment of a variety of symptoms ordisorders. For example, certain embodiments, provide a method fortreatment of T2DM in a patient comprising administering to a subject inneed of such treatment an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof. In an embodiment, is amethod for treatment of obesity in a patient comprising administering toa subject in need of such treatment an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof. In anembodiment, the method is inducing non-therapeutic weight loss in asubject, comprising administering to a subject in need of such treatmentan effective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, the present invention provides a method fortreatment of metabolic syndrome in a patient comprising administering toa subject in need of such treatment an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof. In anembodiment, the method is treatment of NASH comprising administering toa subject in need of such treatment an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof.

Also provided herein is a compound of the present invention for use insimultaneous, separate and sequential combinations with one or moreagents selected from metformin, a thiazolidinedione, a sulfonylurea, adipeptidyl peptidase 4 inhibitor, a sodium glucose co-transporter, aSGLT-2 inhibitor, a growth differentiation factor 15 modulator(“GDF15”), a peptide tyrosine tyrosine modulator (“PYY”), a modifiedinsulin, amylin, a dual amylin calcitonin receptor agonist, andoxyntomodulin agonist (“OXM”) in the treatment of a condition selectedfrom the group consisting of T2DM, obesity, NAFLD, NASH, dyslipidemiaand metabolic syndrome. In an embodiment, a compound of the presentinvention is provided in a fixed dose combination with one or moreagents selected from metformin, a thiazolidinedione, a sulfonylurea, adipeptidyl peptidase 4 inhibitor, a sodium glucose co-transporter, aSGLT-2 inhibitor GDF15, PYY, a modified insulin, amylin, a dual amylincalcitonin receptor agonist, and OXM. In an embodiment is a compound ofthe present invention for use in simultaneous, separate and sequentialcombinations with one or more agents selected from metformin, athiazolidinedione, a sulfonylurea, a dipeptidyl peptidase 4 inhibitor, asodium glucose co-transporter, a SGLT-2 inhibitor, GDF15, PYY, amodified insulin, amylin, a dual amylin calcitonin receptor agonist, andOXM in the treatment of a condition selected from the group consistingof T2DM and obesity. In an embodiment is a compound of the presentinvention for use in simultaneous, separate and sequential combinationswith one or more agents selected from metformin, a thiazolidinedione, asulfonylurea, a dipeptidyl peptidase 4 inhibitor, a sodium glucoseco-transporter, and a SGLT-2 inhibitor in the treatment of a conditionselected from the group consisting of T2DM and obesity.

In other embodiments, the compounds, or a pharmaceutically acceptablesalt thereof, may be useful to improve bone strength in subjects in needthereof. The compounds of the present invention, or a pharmaceuticallyacceptable salt thereof, may be useful in the treatment of otherdisorders such as Parkinson's disease or Alzheimer's disease. Incretinsand incretin analogs having activity at one or more of the GIP, GLP-1and/or glucagon receptors have been described as having the potential tohave therapeutic value in a number of other diseases or conditions,including for example obesity, NAFLD and NASH, dyslipidemia, metabolicsyndrome, bone related disorders, Alzheimer's disease, and Parkinson'sdisease. See, e.g., Jall S., et. al, Monomeric GLP-1/GIP/glucagontriagonism corrects obesity, hepatosteatosis, and dyslipidemia in femalemice, MOL. METAB. 6(5):440-446 (March 2017); Carbone L. J., et. al.,Incretin-based therapies for the treatment of non-alcoholic fatty liverdisease: A systematic review and meta-analysis. J. GASTROENTEROL.HEPATOL., 31(1):23-31 (January 2016); B. Finan, et. al, Reappraisal ofGIP Pharmacology for Metabolic Diseases. TRENDS MOL. MED., 22(5):359-76(May 2016); Choi, I. Y., et al., Potent body weight loss and efficacy ina NASH animal model by a novel long-acting GLP-1/Glucagon/GIPtriple-agonist (HM15211), ADA 2017 Poster 1139-P; Ding, K. H., Impact ofglucose-dependent insulinotropic peptide on age-induced bone loss, J.BONE MINER. RES., 23(4):536-43 (2008); Tai, J. et. al, Neuroprotectiveeffects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PSItransgenic mouse model of Alzheimer's disease, BRAIN RES. 1678, 64-74(2018); T. D. Müller et al., The New Biology and Pharmacology ofGlucagon, PHYSIOL. REV. 97: 721-766 (2017); Finan, B. et. al,Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents,Monkeys, and Humans, SCI. TRANSL. MED., 5:209 (October 2013); HölscherC, Insulin, incretins and other growth factors as potential noveltreatments for Alzheimer's and Parkinson's diseases. BIOCHEM. SOC.TRANS. 42(2):593-0 (April 2014).

Another embodiment provides the use of a compound of the presentinvention, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a condition selectedfrom the group consisting of T2DM, obesity, NAFLD, NASH, dyslipidemiaand metabolic syndrome. In an embodiment, the medicament is for thetreatment of T2DM. In an embodiment, the medicament is for the treatmentof obesity. In an embodiment, the medicament is for the treatment ofNAFLD. In an embodiment, the medicament is for the treatment of NASH.

Another embodiment provides a pharmaceutical composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof,and at least one selected from the group consisting of a carrier,diluent, and excipient.

In an embodiment is a pharmaceutical composition comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, at leastone permeation enhancer and at least one protease inhibitor. In anembodiment, is a pharmaceutical composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof, at least onepermeation enhancer, and at least one selected from the group consistingof carrier, diluent, and excipient.

In an embodiment is a pharmaceutical composition comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, apermeation enhancer, a protease inhibitor, and at least one selectedfrom the group consisting of carrier, diluent, and excipient. In anembodiment is a pharmaceutical composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof, and apermeation enhancer. In an embodiment is a pharmaceutical compositioncomprising a compound of the present invention, or a pharmaceuticallyacceptable salt thereof, and a permeation enhancer. In an embodiment thepermeation enhancer is selected from the group consisting of sodiumdecanoate (“C10”), sodium taurodeoxycholate (“NaTDC”), lauroyl carnitine(“LC”), dodecyl maltoside (“C12-maltoside”), dodecyl phosphatidylcholine(“DPC”), sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (“SNAC”) and aRhamnolipid. In an embodiment the permeation enhancer is selected fromthe group consisting of C10 and LC. In an embodiment a proteaseinhibitor is selected from the group consisting of soybean trypsininhibitor (“SBTI”), soybean trypsin-chymotrypsin inhibitor (“SBTCI”),ecotin, sunflower trypsin inhibitor (“SFTI”), leupeptin, citric acid,ethylenediaminetetraacetic acid (“EDTA”), sodium glycocholate and4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (“AEBSF”). In anembodiment, a protease inhibitor is selected from the group consistingof SBTI, SBTCI, and SFTI. In an embodiment, a protease inhibitor isSBTI.

As used herein, the term “treating” or “to treat” includes restraining,slowing, stopping, or reversing the progression or severity of asymptom, condition, or disorder.

Certain compounds of the present invention are generally effective overa wide dosage range. For example, dosages for once weekly parenteraldosing may fall within the range of 0.05 mg to about 30 mg per personper week.

The compounds of the present invention include novel amino acidsequences having affinity for the respective GLP-1 and GIP receptors,with desired potency at each of these receptors. GLP-1 is a 36 aminoacid peptide, the major biologically active fragment of which isproduced as a 30-amino acid, C-terminal amidated peptide (GLP-1₇₋₃₆)(SEQ ID NO:2).

GIP is a 42 amino acid peptide (SEQ ID NO:1), which, like GLP-1, is alsoknown as an incretin, and plays a physiological role in glucosehomeostasis by stimulating insulin secretion from pancreatic beta cellsin the presence of glucose.

The compounds provide desired potency at each of the GIP and GLP-1receptors. In an embodiment, compounds are suitable for oraladministration. In an embodiment, compounds have desirable GIP and GLPreceptor extended time action. In an embodiment, compounds havedesirable GIP and GLP receptor activity wherein the GIP agonist potencyis from 2.5 to 5 times the GLP1 receptor potency as measured by thecasein cAMP assay described herein below, wherein the potency isnormalized against native GIP and GLP on the day the assay is run. In anembodiment, compounds have desirable GIP and GLP receptor activitywherein the GIP agonist potency is from 2.5 to 10 times the GLP1receptor potency as measured by the casein cAMP assay, wherein thepotency is normalized against native GIP and GLP on the day the assay isrun.

As used herein the term “amino acid” means both naturally occurringamino acids and unnatural amino acids. The amino acids are typicallydepicted using standard one letter codes (e.g., L=leucine), as well asalpha-methyl substituted residues of natural amino acids (e.g., α-methylleucine, or αMeL and α-methyl lysine, or αMeK) and certain otherunnatural amino acids, such as alpha amino isobutyric acid, or “Aib,”“4Pal,” “Orn,” and the like. The structures of these amino acids appearbelow:

As used herein “Orn” means ornithine. As used herein “4Pal” means3-(4-Pyridyl)-L-alanine. As used herein “αMeF(2F)” means alpha-methyl2-F-phenylalanine. As used herein “αMeY,” “αMeK,” and “αMeL” mean alphamethyl tyrosine, alpha methyl lysine, and alpha methyl leucine,respectively. As used herein, “e” and “D-Glu” mean D-glutamic acid. Asused herein “D-His” and “h” each mean D-histidine. As used herein“D-Tyr” and “y” each means D-tyrosine. As used herein “D-Ser” and “s”means means D-serine. As used herein “D-Ala” and “a” each meansD-alanine. As used herein, “αMeF(2F)” means alpha-methyl-F(2F) andalpha-methyl-Phe(2F). As used herein, “αMeF”, means alpha-methyl-F andalpha-methyl-Phe. As used herein, “αMeY”, means alpha-methyl-Tyr. Asused herein “αMeK”, means alpha-methyl-Lys. As used herein, “αMeL”,means alpha-methyl-Leu. As used herein, “αMeS”, meansalpha-methyl-serine and alpha-methyl-Ser. As used herein “αMeP”, meansalpha-methyl-proline and alpha-methyl-Pro. As used herein, “desH”, meansdesHis. As used herein, “desY”, means desTyr.

When X₁ is DesH and X₂ is Aib, and the DesH and Aib can combine to forma group as illustrated above, DesH-ψ[NHCO]-Aib.

When used herein, the term “amino acid conjugated to a C₁₆-C₂₂ fattyacid” refers to any natural or unnatural amino acid with a functionalgroup that has been chemically modified to conjugate to a fatty acid byway of a covalent bond to the fatty acid or, preferably, by way of alinker. Examples of such functional groups include amino, carboxyl,chloro, bromo, iodo, azido, alkynyl, alkenyl, and thiol groups. Examplesof natural amino acids which include such functional groups include K(amino), C (thiol), E (carboxyl) and D (carboxyl). In an embodiment theconjugated amino acid is K.

As noted above, in an embodiment of a compound of Formula I, II, III,IV, and V are compounds of the present invention wherein a fatty acidmoiety is conjugated via a linker or a direct bond. In an embodiment,compounds of the present invention include a fatty acid moietyconjugated, preferably via a linker, to a K at position 14 or 17. In anembodiment, the conjugation is an acylation. In an embodiment, theconjugation is to the epsilon-amino group of the K side-chain. In anembodiment of the compounds of the present invention include a fattyacid moiety conjugated, via a linker, to a K at position 17.

In an embodiment, compounds of the present invention include a fattyacid moiety conjugated directly, without a linker, to a natural orunnatural amino acid with a functional group available for conjugation.In certain preferred embodiments the conjugated amino acid is selectedfrom the group consisting of K, C, E and D. In particularly preferredembodiments the conjugated amino acid is K. In such embodiments, theconjugation is to the epsilon-amino group of the K side-chain.

In an embodiment, the linker comprises one to four amino acids, an aminopolyethylene glycol carboxylate, or mixtures thereof. In an embodiment,the amino polyethylene glycol carboxylate has the following formula:

H—{NH—CH2-CH2-[O—CH2-CH2]_(p)-O—(CH2)_(z)-CO}_(r)—OH, wherein p is anyinteger from 1 to 12, z is any integer from 1 to 20, and r is 1 or 2.

In an embodiment is a compound of Formula I which comprises an aminoacid conjugated to a fatty acid via a linker, wherein the linker is oneto two amino acids selected from the group consisting of Glu and r-Glu.In an embodiment the linker is one to two(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. The compounds of thepresent invention utilize a C₁₆-C₂₂ fatty acid chemically conjugated tothe functional group of an amino acid either by a direct bond or by alinker. In an embodiment, the fatty acid moiety is conjugated to alysine at position 17 via a linker between the lysine and the fattyacid. In an embodiment, the fatty acid moiety is conjugated to a lysineat position 20 via a linker between the lysine and fatty acid. In anembodiment, the fatty acid chain is any single chain C₁₆-C₂₂ fatty acid.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein the fatty acid is conjugated with alinker, and the linker comprises one or more(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties, in combination withzero or one to four amino acids. In an embodiment, the linker maycomprise one to four Glu or γ-Glu amino acid residues. In an embodiment,the linker may comprise 1 or 2 Glu or γ-Glu amino acid residues. In anembodiment is a compound of Formula I, or a pharmaceutically acceptablesalt thereof, comprises a fatty acid conjugated via a linker wherein,the linker comprises either 1 or 2 γ-Glu amino acid residues. In anembodiment is a compound of Formula I, or a pharmaceutically acceptablesalt thereof, comprises a fatty acid conjugated via a linker wherein thelinker may comprise one to four amino acid residues (such as, forexample Glu and r-Glu amino acids) used in combination with up to 36(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. Specifically, in anembodiment is a Formula I compound, or a pharmaceutically acceptablesalt thereof, which comprises a fatty acid conjugated via a linkerwherein, the linker constitutes combinations of one to four Glu andr-Glu amino acids and one to four (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)moieties. In an embodiment is a Formula I compound, or apharmaceutically acceptable salt thereof, which comprises a fatty acidconjugated via a linker wherein the linker is comprised of combinationsof one or two γ-Glu amino acids and one or two(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. In an embodiment is aFormula I compound, or a pharmaceutically acceptable salt thereof, whichcomprises a fatty acid conjugated via a linker wherein the linker andfatty acid components have the following formula:

(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)_(a)-(γ-Glu)_(b)-CO—(CH₂)_(q)—CO₂H,wherein a is 1 or 2, b is 1 or 2 and q is 16 or 18. In an embodiment, ais 2, b is 1 and q is 18; and the structure is:

In an embodiment, a is 1, b is 2 and q is 18; and the structure is:

In an embodiment a is 1, b is 1, and q is 18; and the structure is:

The term “C₁₆-C₂₂ fatty acid” as used herein means a carboxylic acidwith between 16 and 22 carbon atoms. In an embodiment, the C₁₆-C₂₂ fattyacid suitable for use herein can be a saturated diacid. In anembodiment, the fatty acid is C₂₀-C₂₂. In an embodiment q is selectedfrom the group consisting of 14, 16, 18, and 20. In an embodiment q isselected from 18 and 20. In an embodiment q is 18. In an embodiment q is20.

In an embodiment, specific saturated C₁₆-C₂₂ fatty acids that aresuitable for the compounds and uses thereof disclosed herein include,but are not limited to, hexadecanedioic acid (C₁₆ diacid),heptadecanedioic acid (C₁₇ diacid), octadecanedioic acid (Cis diacid),nonadecanedioic acid (C₁₉ diacid), eicosanedioic acid (C₂₀ diacid),heneicosanedioic acid (C₂₁ diacid), docosanedioic acid (C₂₂ diacid),including branched and substituted derivatives thereof.

In an embodiment, the C₁₆-C₂₂ fatty acid is selected from the groupconsisting of a saturated C₁₈ diacid, a saturated C₁₉ diacid, asaturated C₂₀ diacid, and branched and substituted derivatives thereof.In an embodiment, the C₁₆-C₂₂ fatty acid is selected from the groupconsisting of stearic acid, arachadic acid and eicosanedioic acid. In anembodiment, the C₁₆-C₂₂ fatty acid is arachadic acid.

As shown in the chemical structures of Examples 1-5 below, in anembodiment the linker-fatty acid moieties described above link to theepsilon-amino group of the lysine side-chain.

In an embodiment, is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein none of X₃₀, X₃₁, X₃₂, X₃₃, X₃₄, X₃₅,X₃₆, X₃₇, X₃₈, X₃₉, and X₄₀ is C or is a substituent that contains afatty acid. In an embodiment, is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein none of X₁₀, X₁₂, X₁₃,X₁₄, X₁₆, X₁₇, X₁₉, X₂₀, X₂₁, X₂₃, X₂₄, X₂₆, X₂₇, X₂₈, X₂₉, X₃₀, X₃₁,X₃₂, X₃₃, X₃₄, X₃₅, X₃₆, X₃₇, X₃₈, X₃₉, and X₄₀ is a substituent thatcontains a fatty acid; and none of X₃₀, X₃₄, X₃₉, and X₄₀ is C. In anembodiment is a compound of Formula I, or a pharmaceutically acceptablesalt thereof, wherein none of X₁₀, X₁₂, X₁₃, X₁₄, X₁₆, X₁₇, X₁₉, X₂₀,X₂₁, X₂₃, X₂₄, X₂₆, X₂₇, X₂₈, X₂₉, X₃₀, X₃₁, X₃₂, X₃₃, X₃₄, X₃₅, X₃₆,X₃₇, X₃₈, X₃₉, and X₄₀ is a substituent that contains a fatty acid.

As used herein “time-extension technology” means a peptidetime-extension technology for example, recombinant human serum albumin(“rHSA”), peptide conjugation to a pharmaceutically acceptable polymer,such as polymeric sequence of amino acids (“XTEN”), unsulfatedheparin-like carbohydrate polymer (“HEP”), hydroxyl ethyl starch(“HES”), llama heavy-chain antibody fragments (“VHH”), pegylation, Fcconjugation, bovine serum albumin (“BSA”) (Sleep, D. Epert Opin Drug Del(2015) 12, 793-812; Podust V N et. al. J Control. Release, 2015; ePUB;Hey, T. et. al. in: R. Kontermann (Ed.), Therapeutic Proteins:Strategies to Modulate their Plasma Half-Lives, Wiley-VCH Verlag Gmbh &Co. KGaA, Weinheim, Germany, 2012, pp 17-140; DeAngelis, P L, Drug DevDelivery (2013) January, Dec. 31, 2012. In an embodiment time-extensiontechnology is applied using a linker group. In an embodiment, thetime-extension technology is applied using 0, 1, 2, or 3 amino acids aslinker.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, without a fatty acid (i.e., a compound wherenone of X₁₀, X₁₂, X₁₃, X₁₄, X₁₆, X₁₇, X₁₉, X₂₀, X₂₁, X₂₃, X₂₄, X₂₆, X₂₇,X₂₈, X₂₉, X₃₀, X₃₁, X₃₂, X₃₃, X₃₄, X₃₅, X₃₆, X₃₇, X₃₈, X₃₉, and X₄₀ is asubstituent that contains a fatty acid) or time-extension technology maybe administered to a patient in need thereof via transdermal or infusionmethods of administration. Further, a compound of Formula I, or apharmaceutically acceptable salt thereof, without a fatty acid may befurther modified using a peptide time-extension technology for example,recombinant human serum albumin (“rHSA”), peptide conjugation to apharmaceutically acceptable polymer, such as polymeric sequence of aminoacids (“XTEN”), unsulfated heparin-like carbohydrate polymer (“HEP”),and hydroxyl ethyl starch (“HES”). In an embodiment, a time-extensiontechnology is applied using a cysteine amino acid in a Formula Icompound, or a pharmaceutically acceptable salt thereof, without a fattyacid, using procedures known to the skilled artisan. In an embodiment, atime-extension technology is applied to one amino acid in a Formula Icompound, or a pharmaceutically acceptable salt thereof, without a fattyacid. In an embodiment, wherein a time-extension technology is appliedto a Formula I compound, or a pharmaceutically acceptable salt thereof,without a fatty acid, X₁₇ is selected from the group consisting of I, Kand Q. In an embodiment wherein a time-extension technology is appliedto a Formula I compound, or a pharmaceutically acceptable salt thereof,without a fatty acid, X₃₀ is C. In an embodiment wherein atime-extension technology is applied to a Formula I compound, or apharmaceutically acceptable salt thereof, without a fatty acid, X₃₄ isC. In an embodiment wherein a time-extension technology is applied to aFormula I compound, or a pharmaceutically acceptable salt thereof,without a fatty acid, X₃₉ is C. In an embodiment wherein atime-extension technology is applied to a Formula I compound, or apharmaceutically acceptable salt thereof, without a fatty acid, X₄₀ isC.

When used herein in reference to one or more of the GIP or GLP-1receptors, the terms “activity,” “activate[s]” “activat[ing]” and thelike refers to the capacity of a compound, or a pharmaceuticallyacceptable salt thereof, to bind to and induce a response at thereceptor(s), as measured using assays known in the art, such as the invitro assays described below.

The affinity of compounds, or a pharmaceutically acceptable saltthereof, of the present invention for each of the GIP and GLP-1receptors may be measured using techniques known for measuring receptorbinding levels in the art, including, for example those described in theexamples below, and is commonly expressed as a Ki value. The activity ofthe compounds of the present invention at each of the receptors may alsobe measured using techniques known in the art, including for example thein vitro activity assays described below, and is commonly expressed asan EC₅₀ value, which is the concentration of compound causinghalf-maximal simulation in a dose response curve.

In an embodiment, a pharmaceutical composition of a compound of FormulaI is suitable for administration by a parenteral route (e.g.,subcutaneous, intravenous, intraperitoneal, intramuscular, ortransdermal). In an embodiment, a pharmaceutical composition of acompound of Formula I is suitable for oral administration (e.g., tablet,capsule). Some pharmaceutical compositions and processes for preparingsame are well known in the art. (See. e.g., Remington: The Science andPractice of Pharmacy (D. B. Troy, Editor, 21st Edition, Lippincott,Williams & Wilkins, 2006). Physiochemical properties of a peptide inaddition to anatomical and physiological features of thegastrointestinal tract may provide challenges to efficient oral deliveryof a peptide. In an embodiment a pharmaceutical composition for oraladministration comprises of a compound of this invention, and apermeation enhancer. In an embodiment, a pharmaceutical composition fororal administration comprises a compound of Formula I or apharmaceutically acceptable salt thereof, a permeation enharncer, and aprotease inhibitor. In an embodiment, a pharmaceutical composition fororal administration comprises a compound of Formula I, or apharmaceutically acceptable salt thereof, and a permeation enharncer,

Monolithic and multi-particulate dosage forms for compounds of thepresent invention are contemplated. In an embodiment, a compound ofFormula I is provided as a monolithic composition. A monolithiccomposition is intended for release of all components in a singlelocation. A multi-particulate composition is intended to achieve fasttransit from the stomach to the intestine and allow for distribution ofcomposition components over large surface of small intestine. Concurrentrelease of a compound and functional excipients is desired formonolithic and multi-particulate dosage compositions. In an embodiment amonolithic composition of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is formulated as an enteric capsule, entericcoated capsule or an enteric coated tablet. Such multi-particulatecomposition may be formulated as an enteric coated minitablets, orenteric coated granules where the coating is generally intact in thestomach at low pH and dissolves at the higher pH of the intestine. Twotypes of coated minitablets or coated granules may be formulated foreither delivery to proximal small intestine by dissolution above pH 5.5or to distal small intestine by dissolution above pH 7-7.2. A coatingsystem for distal small intestinal release can also be applied tomonolithic capsules or tablets if distal small intestinal delivery isdesired. Minitablets may be filled into a standard uncoated capsule.

As used herein the term “permeation enhancer” means permeation enhancerthat enhances oral absorption of a compound of this invention. As usedherein, permeation enhancer means permeation enhancers, such as sodiumdecanoate, sodium taurodeoxycholate, lauroyl carnitine, dodecylmaltoside, dodecyl phosphatidylcholine, SNAC, a Rhamnolipid, andpermeation enhancers reported in the literature, such as for example,Permeant inhibitor of phosphatase, PIP-250 and PIP-640. See,Pharmaceutics. 2019 January; 11(1): 41, (See Biomaterials. 2012; 33:3464-3474), ZOT (zonula occludens toxin), ΔG (fragment of ZOT) (See Int.J. Pharm. 2009; 365, 121-130). In an embodiment, a permeation enhanceris selected from the group consisting of sodium decanoate, sodiumtaurodeoxycholate, and lauroyl carnitine. In an embodiment, a permeationenhancer is selected from the group consisting of C10, LC, and NaTDC. Inan embodiment a permeation enhancer is C10.

As used herein the term “protease inhibitor” means a protease inhibitorthat may be selected from the group consisting of protein based, peptidebased, and small molecule based. Protease inhibitors are well known andmay include, for example, soybean trypsin inhibitor (“SBTI”), soybeantrypsin-chymotrypsin inhibitor (“SBTCI”), ecotin, sunflower trypsininhibitor (“SFTF”), leupeptin, citric acid, ethylenediaminetetraaceticacid (“EDTA”), sodium glycocholate and 4-(2-aminoethyl)benzenesulfonylfluoride hydrochloride (“AEBSF”). In an embodiment a protease inhibitoris selected from the group consisting of SBTI, SBTCI and SFTI. In anembodiment, a protease inhibitor is SBTI.

In an embodiment is a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein the compound is a potent GIPR/GLP-1Rdual agonist that is a partial agonist on the GLP-1R as demonstrated bya Cell Membrane Guanosine 5′-(gamma-thio) Triphosphate-[³⁵S](GTPγS)Binding Assay, and a partial agonist on the GLP-1R as demonstrated by aβ-arrestin-2 recruitment assay. In an embodiment is a compound ofFormula I, or pharmaceutically acceptable salt thereof, wherein thecompound stimulates GLP-1R induced activation of Gas in the GLP-1RHEK293 Cell Membrane Guanosine 5′-(gamma-thio) Triphosphate-[³⁵S](GTPγS)Binding Assay. In an embodiment, is a compound showing partial agonismof 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine5′-(gamma-thio) Triphosphate-[³⁵S] (GTPγS) Binding Assay, and 35% orless in the GLP-CHO Cell β-Arrestin.Recruitment Assay.

In an embodiment is a method for treating diabetes comprisingadministering an effective amount of a compound showing partial agonismof 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine5′-(gamma-thio) Triphosphate-[³⁵S] (GTPγS) Binding Assay, and aneffective amount of a compound that is a GIP agonist. In an embodiment,the compound showing partial agonism in the GLP-1R HEK293 Cell MembraneGuanosine 5′-(gamma-thio) Triphosphate-[³⁵S] (GTPγS) Binding Assay isco-administered with a compound having GIP agonist activity. In anembodiment, the compound showing partial agonism in the GLP-1R HEK293Cell Membrane Guanosine 5′-(gamma-thio) Triphosphate-[³⁵S] (GTPγS)Binding Assay is administered as an active agent within one week beforeor after a compound having GIP agonist activity. In an embodiment, amethod for treating diabetes comprises administering an effective amountof a compound showing 35% or less in the GLP-CHO Cellβ-Arrestin.Recruitment Assay and administering an effective amount of acompound showing partial agonism of 75% or less in the GLP-1R HEK293Cell Membrane Guanosine 5′-(gamma-thio) Triphosphate-[³⁵S] (GTPγS)Binding Assay.

Compounds of the present invention may react with any of a number ofinorganic and organic acids/bases to form pharmaceutically acceptableacid/base addition salts. Pharmaceutically acceptable salts and commonmethodology for preparing them are well known in the art. (See, e.g., P.Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selectionand Use, 2nd Revised Edition (Wiley-VCH, 2011)). Pharmaceuticallyacceptable salts of the present invention include, but are not limitedto, sodium, trifluoroacetate, hydrochloride, ammonium, and acetatesalts. In an embodiment, a pharmaceutically acceptable salt of isselected from the group consisting of sodium, hydrochloride, and acetatesalts.

The present invention also encompasses novel intermediates and processesuseful for the synthesis of compounds of the present invention, or apharmaceutically acceptable salt thereof. The intermediates andcompounds of the present invention may be prepared by a variety ofprocedures known in the art. In particular, the Examples below describea process using chemical synthesis. The specific synthetic steps foreach of the routes described may be combined in different ways toprepare compounds of the present invention. The reagents and startingmaterials are readily available to one of ordinary skill in the art.

When used herein, the term “effective amount” refers to the amount ordose of a compound of the present invention, or a pharmaceuticallyacceptable salt thereof, which, upon single or multiple doseadministration to the patient, provides the desired effect in thepatient under diagnosis or treatment. An effective amount can bedetermined by a person of skill in the art using known techniques and byobserving results obtained under analogous circumstances. In determiningthe effective amount for a subject, a number of factors are considered,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease or disorder involved; the degree ofor involvement or the severity of the disease or disorder; the responseof the individual patient; the particular compound administered; themode of administration; the bioavailability characteristics of thepreparation administered; the dose regimen selected; the use ofconcomitant medication; and other relevant circumstances.

When used herein, the term “subject in need thereof” refers to a mammal,preferably a human, with a disease or condition requiring treatment ortherapy, including for example those listed in the preceding paragraphs.As used herein “EDTA” means ethylenediaminetetraacetic acid. As usedherein “DMSO” means dimethyl sulfoxide. As used herein “CPM” meanscounts per minute. As used herein “IBMX” means3-isobutyl-1-methylxanthine. As used herein “LC/MS” means liquidchromatography/mass spectrometry. As used herein “HTRF” meanshomogeneous time-resolved fluorescence. As used herein “BSA” mean bovineserum albumin.

The invention is further illustrated by the following examples, whichare not to be construed as limiting.

PEPTIDE SYNTHESIS Example 1Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂(SEQ ID NO:10)

The structure of SEQ ID NO: 10 is depicted below using the standardsingle letter amino acid codes with the exception of residues Aib2,αMeF(2F)6, αMeL13, K17, Aib20, D-Glu24, and Ser39 where the structuresof these amino acid residues have been expanded:

The peptide backbone of Example 1 is synthesized usingFluorenylmethyloxycarbonyl (Fmoc)/tert-Butyl (t-Bu) chemistry on aSymphony X peptide synthesizer (Gyros Protein Technologies. Tucson,Ariz.).

The resin consists of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHALow Loading resin, 100-200 mesh, EMD Millipore) at a substitution of0.3-0.4 meq/g. Standard side-chain protecting groups were used.Fmoc-Lys(Mtt)-OH is used for the lysine at position 17 andBoc-Tyr(tBu)-OH) was used for the tyrosine at position 1. Fmoc groupsare removed prior to each coupling step (2×7 minutes) using 20%piperidine in DMF. All standard amino acid couplings are performed for 1hour to a primary amine and 3 hour to a secondary amine, using an equalmolar ratio of Fmoc amino acid (0.3 mM), diisopropylcarbodiimide (0.9mM) and Oxyma (0.9 mM), at a 9-fold molar excess over the theoreticalpeptide loading. Exceptions are couplings to Cα-methylated amino acids,which are coupled for 3 hours. After completion of the synthesis of thepeptide backbone, the resin is thoroughly washed with DCM for 6 times toremove residual DMF. The Mtt protecting group on the lysine at position17 is selectively removed from the peptide resin using two treatments of300 hexafluoroisopropanol (Oakwood Chemicals) in DCM (2×40-minutetreatment).

Subsequent attachment of the fatty acid-linker moiety is accomplished bycoupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid(Fmoc-AEEA-OH, ChemPep, Inc.), Fmoc-glutamic acid α-t-butyl ester(Fmoc-Glu-OtBu, Ark Pharm, Inc.), mono-OtBu-eicosanedioic acid (WuXiAppTec, Shanghai, China). 3-Fold excess of reagents(AA:PyAOP:DIPEA=1:1:1 mol/mol) are used for each coupling that is 1-hourlong.

After the synthesis is complete, the peptide resin is washed with DCM,and then thoroughly air-dried. The dry resin is treated with 10 mL ofcleavage cocktail (trifluoroacetic acid:water:triisopropylsilane,95:2.5:2.5 v/v) for 2 hours at room temperature. The resin is filteredoff, washed twice each with 2 mL of neat T′FA, and the combinedfiltrates are treated with 5-fold excess volume of cold diethyl ether(−20° C.) to precipitate the crude peptide. The peptide/ether suspensionis then centrifuged at 3500 rpm for 2 min to form a solid pellet, thesupernatant is decanted, and the solid pellet is triturated with ethertwo additional times and dried in vacuo. The crude peptide issolubilized in 20% acetonitrile/20% Acetic acid/60% water and purifiedby RP-HPLC on a Luna 5 μm Phenyl-Hexyl preparative column (21×250 mm,Phenomenex) with linear gradients of 100% acetonitrile and 0.1%TFA/water buffer system (30-50% acetonitrile in 60 min). The purity ofpeptide is assessed using analytical RP-HPLC and pooling criteriais >95%. The main pool purity of compound 1 is found to be 98.0%.Subsequent lyophilization of the final main product pool yielded thelyophilized peptide TFA salt. The molecular weight is determined byLC-MS (obsd. M+3=1657.2; Calc M+3=1657.0).

Example 2Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂(SEQ ID NO:11)

The structure of SEQ ID NO: 11 is depicted below using the standardsingle letter amino acid codes with the exception of residues Aib2,αMeF(2F)6, αMeL13, Orn16, K17, Aib20 D-Glu24, and Ser39 where thestructures of these amino acid residues have been expanded:

The compound according to SEQ ID NO: 11 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1642.6; Calc M+3=1642.8).

Example 3

Example 3 is a compound represented by the following description:

Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂(SEQ ID NO:12)

The structure of SEQ ID NO: 12 is depicted below using the standardsingle letter amino acid codes with the exception of residues Aib2,αMeF(2F)6, αMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where thestructures of these amino acid residues have been expanded:

The compound according to SEQ ID NO: 12 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1651.8; Calc M+3=1652.2).

Example 4Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxyl]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH₂(SEQ ID NO:13)

The structure of SEQ ID NO: 13 is depicted below using the standardsingle letter amino acid codes with the exception of residues Aib2,αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24 αMeY25, and Ser39,where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO: 13 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1642.5; Calc M+3=1642.1)

Example 5Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH₂(SEQ ID NO:14)

The structure of SEQ ID NO: 14 is depicted below using the standardsingle letter amino acid codes with the exception of residues Aib2,αMeF(2F)6, αMeL13, Orn16, K17, Aib20, D-Glu24,αMeY25, and Ser39, wherethe structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO: 14 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1626.1; Calc M+3=1626.1).

Example 6 Through Example 287

The compounds according to Examples 6 (SEQ ID NO: 15) through Example287 (SEQ ID NO:296) are prepared substantially as described by theprocedures of Example 1.

Calculated Found SEQ MW MW Example Compound Name ID NO (average)(average) 6 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 15 4863.5 4862.1Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH₂ 7 Y-Aib-EGTFTSDYSILLDSK((2-[2-(2- 16 4822.44821.3 Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH₂ 8 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 17 4863.54863.2 Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 9 Y-Aib-EGTFTSDYSILLDSK((2-[2-(2- 18 4822.44820.7 Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 10 Y-Aib-EGTFTSDYSILLDSIAQ-Aib- 19 4776.5 4775.4AFIK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)YLLA- Aib-GPSSGAPPPS-NH₂ 11Y-Aib-EGTFTSDYSILLDSIAQ-Aib- 20 4834.5 4834.8AFIEYLLK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)- Aib-GPSSGAPPPS-NH₂ 12Y-Aib-EGTFTSDYSILLDKIAQK((2-[2-(2- 21 4891.6 4890.0Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)-AFIEYLIEGGPSSGAPPPS- NH₂ 13 Y-Aib-EGTFTSDYSILLD-Aib-IAQK((2-[2- 224848.5 4846.8 (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)- AFIEYLIEGGPSSGAPPPS-NH₂ 14Y-Aib-EGTFTSDYSILLDKIAQK((2-[2-(2- 23 4976.7 4975.5Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) EFIQYLLE-Aib-GPSSGAPPPS-NH₂ 15 H-Aib-EGTFTSDYSILLDKK((2-[2-(2- 24 4865.5 4863.9Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLLE-Aib- GPSSGAPPPS-NH₂ 16 H-Aib-EGTFTSDYSILLDKK((2-[2-(2-25 4865.5 4863.9 Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIE-Aib- GPSSGAPPPS-NH₂ 17H-Aib-EGTFTSDYSILLDKIAQK((2-[2-(2- 26 4444.1 4442.7Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AFIEYLLE-Aib-GPSSG-NH₂ 18 H-Aib-EGTFTSDYSI-αMeL-LDKK(Dab-(2- 27 4979.84978.8 [2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Dab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO—(CH₂)₁₈—CO₂H)AQ-αMeK-AFIQYLLA-Aib- GPSSGAPKPS-NH₂ 19H-Aib-EGTFTSDYSI-αMeL-LDKK(Dab-(2- 28 4948.8 4947.2[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Dab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO—(CH₂)₁₈—CO₂H)AQ-αMeK-AFIQYLLA-Aib- GPSSGAPPPS-NH₂ 20Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 29 4877.5 4875.9(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 21 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 30 4935.64934.1 (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-αMeK- AFIEYLLEGGPSSGAPPPS-NH₂ 22Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 31 4963.6 4962.0(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-αMeK-AFIEYLLE- Aib-GPSSGAPPPS-NH₂ 23Y-Aib-EGTFTSDK((2-[2-(2-Amino-ethoxy)- 32 4813.5 4812.9ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) SILLDKIAQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 24 Y-Aib-EGTFTSDYK((2-[2-(2-Amino- 33 4889.64888.6 ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) ILLDKIAQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 25 Y-Aib-EGTFTSDYSK((2-[2-(2-Amino- 34 4863.54862.5 ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) LLDKIAQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 26 Y-Aib-EGTFTSDYSIK((2-[2-(2-Amino- 35 4863.5N/I ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) LDKIAQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 27 Y-Aib-EGTFTSDYSILK((2-[2-(2-Amino- 36 4863.5N/I ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) DKIAQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 28 Y-Aib-EGTFTSDYSILLK((2-[2-(2-Amino- 37 4861.6N/I ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) KIAQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 29 Y-Aib-EGTFTSDYSILLDK((2-[2-(2-Amino- 384848.5 N/I ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)IAQ-Aib-AFIEYLIEGGPSSGAPPPS- NH₂ 30 Y-Aib-EGTFTSDYSILLDKIK((2-[2-(2- 394905.6 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)Q-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 31 Y-Aib-EGTFTSDYSILLDKIAK((2-[2-(2- 404848.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)- Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 32 Y-Aib-EGTFTSDYSILLDKIAQ-Aib-K((2- 41 4905.6N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ- Glu)-CO—CH₂)₁₈—CO₂H)FIEYLIEGGPSSGAPPPS-NH₂ 33 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 42 4863.5 N/IAFK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)EYLIEGGPSSGAPPPS-NH₂ 34 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 43 4847.6 N/IAFIK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)YLIEGGPSSGAPPPS-NH₂ 35 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 44 4863.5 N/IAFIEYK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)IEGGPSSGAPPPS-NH₂ 36 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 45 4863.5 N/IAFIEYLK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) EGGPSSGAPPPS-NH₂ 37Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 46 4847.6 N/IAFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) GGPSSGAPPPS-NH₂ 38Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 47 4919.6 N/IAFIEYLIEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) GPSSGAPPPS-NH₂ 39Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 48 4919.6 N/IAFIEYLIEGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) PSSGAPPPS-NH₂ 40Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 49 4879.5 N/IAFIEYLIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) SSGAPPPS-NH₂ 41Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 50 4889.6 N/IAFIEYLIEGGPK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) SGAPPPS-NH₂ 42Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 51 4889.6 N/IAFIEYLIEGGPSK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) GAPPPS-NH₂ 43Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 52 4919.6 N/IAFIEYLIEGGPSSK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) APPPS-NH₂ 44Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 53 4905.6 N/IAFIEYLIEGGPSSGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) PPPS-NH₂ 45Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 54 4879.5 N/IAFIEYLIEGGPSSGAK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) PPS-NH₂ 46Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 55 4879.5 N/IAFIEYLIEGGPSSGAPK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) PS-NH₂ 47Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 56 4879.5 N/IAFIEYLIEGGPSSGAPPK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)S—NH₂ 48Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 57 4889.6 N/IAFIEYLIEGGPSSGAPPPK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)—NH₂ 49Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 58 4976.7 N/IAFIEYLIEGGPSSGAPPPSK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)—NH₂ 50Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 59 4414.0 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSG- NH₂ 51 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 60 4085.7N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGG-NH₂ 52 Y-Aib-EGTFTSDYSI-αMeL-LDSK((2-[2-(2- 61 4836.4N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 53 H-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 62 4851.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 54 H-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 63 4903.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQHAFIEYLIEGGPSSGAPPPS-NH₂ 55 H-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 644904.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQHAFIEYLIEGGPSSGAPPPS-NH₂ 56 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 654930.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQHAFIEYLIEGGPSSGAPPPS-NH₂ 57 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 664877.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 58Y-Aib-EGTFTSDYSSLLDKK((2-[2-(2- 67 4837.4 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 59 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 68 4878.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 60 Y-Aib-EGTFTSDYSI-αMeL-LD-Aib-K((2- 69 4834.5N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 61Y-Aib-EGTFTSDYSI-αMeL-LDSK((2-[2-(2- 70 4836.4 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH₂ 62 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 71 4099.7N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGG- NH₂ 63Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 72 4100.6 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGG- NH₂ 64Y-Aib-EGTFTSDYSI-αMeL-LDSK((2-[2-(2- 73 4058.6 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGG-NH₂ 65 Y-Aib-EGTFTSDYSI-αMeL-LDTK((2-[2- 74 4072.6 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGG- NH₂ 66Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 75 4878.5 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH₂ 67 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 76 4877.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-A-αMeF-IEYLIEGGPSSGAPPPS-NH₂ 68 Y-Aib-EGTFTSDY-αMeS-ILLDKK((2-[2- 77 4877.5 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 69 Y-Aib-EGT-αMeF-TSDYSI-αMeL- 78 4891.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 70Y-Aib-EGTFTSDK((2-[2-(2-Amino-ethoxy)- 79 4035.7 N/Iethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) SILLDKIAQ-Aib-AFIEYLIEGG-NH₂71 Y-Aib-EGTFTSDYSILK((2-[2-(2-Amino- 80 4085.7 N/Iethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)DKIAQ-Aib-AFIEYLIEGG-NH₂ 72 Y-Aib-EGTFTSDYSILLDKIAQ-Aib-K((2- 81 4127.8N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)FIEYLIEGG-NH₂ 73 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 824069.7 N/I AFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)GG-NH₂ 74Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 83 4891.6 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-A-αMeF- IEYLIEGGPSSGAPPPS-NH₂ 75Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 84 4891.6 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEY-αMeL- IEGGPSSGAPPPS-NH₂ 76Y-Aib-EGT-aMeF-TSDYSI-αMeL- 85 4905.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- A-αMeF-IEYLIEGGPSSGAPPPS-NH₂ 77Y-Aib-EGTFTSDYSILLKIAQ-Aib- 86 4764.5 N/IAFIEYLIEGGPSSGAPPK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)S—NH₂ 78(D-Tyr)-Aib-EGTFTSDYSILLDKK((2-[2-(2- 87 4863.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 79 Ac-(D-Tyr)-AEGTFTSDYSILLDKK((2-[2- 88 4891.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 80 Y-(D-Ala)-EGTFTSDYSILLDKK((2-[2-(2- 89 4849.5N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 81 Y-Aib-EGTFTSDY-(D-Ser)-ILLDKK((2-[2- 904863.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 82Y-Aib-EGTFTSDYS-(D-Ile)-LLDKK((2-[2- 91 4863.5 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 83 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 92 4863.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLI-(D-Glu)- GGPSSGAPPPS-NH₂ 84Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 93 4863.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFI-(D-Glu)- YLIEGGPSSGAPPPS-NH₂ 85Y-Aib-EGTFTSDASILLDKK((2-[2-(2- 94 4771.4 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 86 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 95 4877.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEAGPSSGAPPPS-NH₂ 87 Y-αMePro-EGTFTSDYSILLDKK((2-[2-(2- 96 4889.5N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 88 Y-Pro-EGTFTSDYSILLDKK((2-[2-(2- 97 4875.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 89 Y-Aib-Aad-GTFTSDYSILLDKK((2-[2-(2- 98 4877.5N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 90 Y-Aib-NGTFTSDYSILLDKK((2-[2-(2- 99 4848.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 91 Y-Aib-(γ-Glu)-GTFTSDYSILLDKK((2-[2- 1004863.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 92Y-Aib-EGT-αMeF-TSDK((2-[2-(2-Amino- 101 4049.7 N/Iethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)SILLDKIAQ-Aib-AFIEYLIEGG-NH₂ 93 Y-Aib-EGT-αMeF-TSDYSILK((2-[2-(2- 1024099.7 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)DKIAQ-Aib-AFIEYLIEGG- NH₂ 94 Y-Aib-EGT-αMeF-TSDYSILLDKIAQ-Aib- 1034141.8 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)FIEYLIEGG-NH₂ 95Y-Aib-EGT-αMeF-TSDYSILLDKIAQ-Aib- 104 4083.7 N/IAFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)GG-NH₂ 96Y-Aib-EGTFTSDK((2-[2-(2-Amino-ethoxy)- 105 4049.7 N/Iethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) SI-αMeL-LDKIAQ-Aib-AFIEYLIEGG-NH₂ 97 Y-Aib-EGTFTSDYSI-αMeL-LDKIAQ-Aib- 106 4083.7 N/IAFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)GG-NH₂ 98Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 107 4099.7 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGG- NH₂ 99 Y-Aib-EGT-αMeF-TSDYSI-αMeL-108 4113.7 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGG-NH₂ 100Y-Aib-EGT-αMeF-TSDYSI-αMeL- 109 4114.7 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGG-NH₂ 101Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib- 110 4090.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGG-NH₂ 102Y-Aib-EGT-αMeF-TSDYSI-Aib-LDEK((2- 111 4072.6 N/I[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ- Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGG-NH₂ 103 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 112 4190.7 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGG-NH₂ 104Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 113 4162.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFIEYLIEGG-NH₂ 105DesHis-ψ[NHCO]-Aib- 114 4822.5 N/I EGTFTSDYSILLDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS- NH₂ 106 DesHis-Aib-EGTFTSDYSILLDKK((2-[2-(2-115 4822.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 107 DesTyr-Aib-EGTFTSDYSILLDKK((2-[2-(2-116 4848.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 108 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 1174859.6 N/I Amino-ethoxy)-ethoxy]-acetyl)-AOC-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 109Y-Aib-EGTFTSDYSILLDKK(AOC-(2-[2-(2- 118 4859.6 N/IAmino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH2 110 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 119 N/IAmino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- (Trx)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 111 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 120 N/IAmino-ethoxy)-ethoxy]-acetyl)-(Trx)-(γ- Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 112 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 121 4846.5N/I Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 113 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 122 4862.6N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 114 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 123 4845.6N/I Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(εK)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 115 Y-Aib-EGT-αMeF-TSDYSI-αMeL- 124 4892.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 116Y-Aib-EGT-αMeF-TSDYSI-αMeL- 125 4950.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 117Y-Aib-EGT-αMeF-TSDYSI-Aib-LDEK((2- 126 4850.4 N/I[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ- Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 118 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 127 4968.5N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 119F-Aib-EGT-αMeF-TSDYSI-αMeL- 128 4876.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 120Y-Aib-cTA-GT-αMeF-TSDYSI-αMeL- 129 4902.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 121Y-Aib-EGT-αMeF-TSDYSI-αMeL- 130 4935.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQQAFIEYLIEGGPSSGAPPPS-NH₂ 122 Y-Aib-EGT-αMeF-TSDYSI-αMeL- 131 4963.6N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQQAFIEYLIE-Aib-GPSSGAPPPS- NH₂ 123Y-Aib-EGT-αMeF-TSDYSI-αMeL- 132 4500.1 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSG-NH₂ 124Y-Aib-EGT-αMeF-TSDYSI-αMeL- 133 4501.0 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSG-NH₂ 125Y-Aib-EGT-αMeF-TSDYSI-αMeL- 134 5020.7 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)₂-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 126Y-Aib-EGT-αMeF-TSDYSI-αMeL- 135 4905.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEAGPSSGAPPPS-NH₂ 127Y-Aib-EGT-αMeF-TSDISILLDKK((2-[2-(2- 136 4827.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 128 Y-Aib-EGT-αMeF-TSDHSILLDKK((2-[2- 137 4851.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 129 Y-Aib-EGT-αMeF-TSDLSILLDKK((2-[2- 138 4827.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 130 Y-Aib-EGT-αMeF-TSDESILLDKK((2-[2- 139 4843.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 131 Y-Aib-EGT-αMeF-TSD-αMeF- 140 4875.6 N/ISILLDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 132Y-Aib-EGT-αMeF-TSD-3Pal-SILLDKK((2- 141 4862.5 N/I[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ- Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 133 DesTyr-Aib-EGT-αMeF-TSDYSI-Aib- 142 4835.4N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 134DesTyr-Aib-EGT-αMeF(2F)-TSDYSI- 143 4953.5 N/IαMeL-LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-EFIEYLIEGGPSSGAPPPS-NH₂ 135 H-Aib-NGTFTSDYSILLDKK((2-[2-(2- 144 4822.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 136 Y-Aib-EGTFTSDASILLDKK((2-[2-(2- 145 4785.4N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-AFIEYLIEAGPSSGAPPPS-NH₂ 137 Y-Aib-EGT-αMeF-TSDYSI-αMeL- 146 4963.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- Aad-FIEYLIEGGPSSGAPPPS-NH₂ 138Y-Aib-EGT-αMeF-TSDYSI-αMeL- 147 4907.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- SFIEYLIEGGPSSGAPPPS-NH₂ 139Y-Aib-EGT-αMeF-TSDYSI-αMeL- 148 4921.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFIEYLIEGGPSSGAPPPS-NH₂ 140Y-Aib-EGT-αMeF-TSDYSI-αMeL- 149 4935.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- DFIEYLIEGGPSSGAPPPS-NH₂ 141Y-Aib-EGT-αMeF-TSDYSI-αMeL- 150 4933.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- IFIEYLIEGGPSSGAPPPS-NH₂ 142Y-Aib-EGT-αMeF-TSDYSI-αMeL- 151 4957.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- HFIEYLIEGGPSSGAPPPS-NH₂ 143Y-Aib-EGT-αMeF-TSDYSI-αMeL- 152 4905.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- Aib-FIEYLIEGGPSSGAPPPS-NH₂ 144Y-Aib-EGT-αMeF-TSDYSI-αMeL- 153 4957.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQH- Aib-FIEYLIEGGPSSGAPPPS-NH₂ 145Y-Aib-EGT-αMeF-TSDASI-αMeL- 154 4799.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 146Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 155 4967.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIQYLIEGGPSSGAPPPS-NH₂ 147Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 156 4982.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-Aad-YLIEGGPSSGAPPPS-NH₂ 148Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 157 4910.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIAYLIEGGPSSGAPPPS-NH₂ 149Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 158 4938.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIVYLIEGGPSSGAPPPS-NH₂ 150Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 159 4926.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFISYLIEGGPSSGAPPPS-NH₂ 151Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 160 4936.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIPYLIEGGPSSGAPPPS-NH₂ 152Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 161 4924.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-Aib-YLIEGGPSSGAPPPS-NH₂ 153Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 162 4976.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIHYLIEGGPSSGAPPPS-NH₂ 154Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 163 4942.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 155Y-Aib-EGT-αMeF(2F)-TSD-cTA-SI-αMeL- 164 4944.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 156Y-Aib-EGT-αMeF(2F)-TSD-2Pal-SI-αMeL- 165 4953.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 157Y-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeL- 166 4953.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 158Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 167 4953.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 159Y-Aib-EGT-αMeF(2F)-TSD-αMeF-SI- 168 4938.5 N/IαMeL-LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQ-Aib-EFIEYLIEGGPSSGAPPPS-NH₂ 160 Y-Aib-EGT-αMeF(2F)-TSD-Aib-SI-αMeL- 169 4862.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂161 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 170 4594.1 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)₂-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSG-NH₂ 162Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 171 4568.1 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)₂-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-HLIEGGPSSG-NH₂ 163H-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 172 4942.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH₂ 164Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 173 4914.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-TFI-(D-Glu)-YLI-(D-Glu)-GGPSSGAPPPS- NH₂ 165Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 174 4912.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-αMeF-LI-(D-Glu)-GGPSSGAPPPS-NH₂ 166 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 175 4136.7 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGG-NH₂ 167Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 176 4465.0 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSG-NH₂ 168Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 177 4914.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂169 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 178 4886.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂170 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 179 4858.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₄—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂171 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL-LD- 180 4899.5 N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂172 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL-LD- 181 4885.5 N/IDab-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂173 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL-LD- 182 4871.5 N/IDap-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂174 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 183 4785.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₈—CO₂H)AQ-Aib-TFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 175Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 184 4913.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂176 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 185 4885.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂177 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 186 4922.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- HFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂178 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 187 4894.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₄—CO₂H)AQ-Aib- HFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂179 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 188 4473.0 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- HFI-(D-Glu)-YLIEGGPSSG-NH₂ 180Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeL- 189 4144.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- HFI-(D-Glu)-YLIEGG-NH₂ 181Y-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeL- 190 4953.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂182 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 191 4953.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂183 Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeL- 192 4918.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂184 Y-Aib-EGT-αMeF(2F)-TSD-(D-Tyr)-SI-αMeL- 193 4968.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂185 Y-Aib-EGT-αMeF(2F)-TSD-(D-His)-SI-αMeL- 194 4942.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂186 Y-Aib-EGT-αMeF(2F)-TSD-αMeY-SI-αMeL- 195 4982.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂187 Y-Aib-EGT-αMeF(2F)-TSDQSI-αMeL- 196 4933.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂188 Y-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeL- 197 4909.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-Aib-YLIEGGPSSGAPPPS-NH₂ 189Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 198 4909.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-Aib-YLIEGGPSSGAPPPS-NH₂ 190H-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeL- 199 4927.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂191 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL- 200 4904.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂192 Y-Aib-EGT-αMeF(2F)-TSDASI-αMeL- 201 4876.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂193 Y-αMePro-EGTFTSDYSILLDEK((2-[2-(2- 202 4933.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQQAFIEYLIEGGPSSGAPPPS-NH₂ 194 Y-αMePro-EGTFTSDYSILLDEK((2-[2-(2- 2034942.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQHAFIEYLIEGGPSSGAPPPS-NH₂ 195 Y-αMePro-EGTFTSDYSILLDRK((2-[2-(2- 2044960.6 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQQAFIEYLIEGGPSSGAPPPS-NH₂ 196 Y-αMePro-EGTFTSDYSILLDRK((2-[2-(2- 2054969.6 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQHAFIEYLIEGGPSSGAPPPS-NH₂ 197 Y-αMePro-EGTFTSDYSILLDEK((2-[2-(2- 2064456.0 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQQAFIEYLIEGGPSSG- NH₂ 198 (D-Tyr)-αMePro-EGTFTSDYSILLDEK((2- 207 4456.0N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ- Glu)-CO—(CH₂)₁₆—CO₂H)AQQAFIEYLIEGGPSSG-NH₂ 199 DesTyr-Aib-EGTFTSDYSILLDEK((2-[2-(2- 2084892.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQQAFIEYLIEGGPSSGAPPPS-NH₂ 200 DesTyr-AEGTFTSDYSILLDEK((2-[2-(2- 2094878.4 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQQAFIEYLIEGGPSSGAPPPS-NH₂ 201 DesHis-αMePro-EGTFTSDYSILLDEK((2- 2104892.5 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H) AQQAFIEYLIEGGPSSGAPPPS-NH₂ 202Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 211 4938.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂203 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 212 4952.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂204 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 213 4924.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂205 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 214 4795.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 206Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 215 4823.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 207Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 216 4923.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂208 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 217 4912.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₄—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂209 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 218 4911.4 N/IDab-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂210 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 219 4897.5 N/IDap-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂211 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 220 4953.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂212 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 221 4967.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂213 Y-Aib-EGT-αMeF-TSDYSI-αMeL- 222 4922.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂214 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 223 4811.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 215Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 224 4839.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 216Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 225 4967.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂217 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 226 4939.5 N/IDab-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂218 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 227 4925.5 N/IDap-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂219 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 228 4491.0 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSG-NH₂ 220Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 229 4162.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGG-NH₂ 221Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 230 4940.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂222 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 231 4982.6 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 223 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-232 4982.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFIE-αMeY-LIEGGPSSGAPPPS-NH₂224 Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib- 233 4926.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂225 Y-Aib-EGT-αMeF-TSDYSI-Aib-LDEK((2- 234 4908.5 N/I[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 226Y-Aib-EGT-αMeF(2F)-TSDYSILLDEK((2- 235 4954.5 N/I[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 227Y-Aib-EGT-αMeF-TSDYSI-αMeL- 236 4950.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂228 Y-Aib-EGT-αMeF-TSDYSI-αMeL- 237 4500.1 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSG-NH₂ 229Y-Aib-EGT-αMeF(2F)-TSDYS-αMeL- 238 4855.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂230 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 239 4976.6 N/ILDHK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂231 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 240 4939.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂232 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 241 4910.5 N/ILD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂233 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 242 4896.5 N/ILD-Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂234 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SILLD- 243 4882.4 N/IDab-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂235 Y-Aib-EGT-αMeF-TSD-4Pal-SI-αMeL-LD- 244 4878.5 N/IDab-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂236 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 245 4939.5 N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 237Y-Aib-EGT-αMeF(2F)-TSDASI-αMeL-LD- 246 4847.4 N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 238Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeL-LD- 247 4889.5 N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 239Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 248 4896.5 N/ILD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 240Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 249 4866.5 N/ILD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 241Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD- 250 N/I N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 242Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD- 251 N/I N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 243Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeL-LD- 252 N/I N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 244Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeL-LD- 253 N/I N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 245Y-Aib-EGT-αMeF(2F)-TSDASI-αMeL-LD- 254 N/I N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 246Y-Aib-EGT-αMeF(2F)-TSDASI-αMeL-LD- 255 N/I N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH₂ 247Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib-LD- 256 4883.4 N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂248 Y-Aib-EGT-αMeF(2F)-TSDYSILLD-Orn- 257 4911.5 N/IK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 249Y-Aib-EGT-αMeF(2F)-TSDYSI-Nle-LD- 258 4911.5 N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂250 Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib-LD- 259 4911.5 N/IOrn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂251 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 260 4893.6 N/ILD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH₂ 252 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 261 4835.6 N/ILD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(εK)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFI-(D-Glu)-αMeY-LIAGGPSSGAPPPS-NH₂ 253 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 262 4849.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQAAFIEYLIEGGPSSGAPPPS-NH₂ 254 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2634906.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQQAFIEYLIEGGPSSGAPPPS-NH₂ 255 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2644915.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQHAFIEYLIEGGPSSGAPPPS-NH₂ 256 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2654906.6 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQKAFIEYLIEGGPSSGAPPPS-NH₂ 257 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2664934.6 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQRAFIEYLIEGGPSSGAPPPS-NH₂ 258 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 2674907.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQKAFIEYLIEGGPSSGAPPPS-NH₂ 259 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 2684864.4 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 260 Y-Aib-EGTFTSDHSILLDKK((2-[2-(2- 2694837.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 261 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2704907.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQEAFIEYLIEGGPSSGAPPPS-NH₂ 262 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2714879.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQTAFIEYLIEGGPSSGAPPPS-NH₂ 263 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2724865.5 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQSAFIEYLIEGGPSSGAPPPS-NH₂ 264 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 2734475.0 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSG-NH₂265 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 274 4146.7 N/ILD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGG-NH₂ 266Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 275 4385.94 4386.6Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFIEYLIEGGPSSG- NH₂ 267 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2764057.62 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFIEYLIEGG-NH₂ 268 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 277 4386.88N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFIEYLIEGGPSSG- NH₂ 269 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 2784058.56 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFIEYLIEGG-NH₂ 270 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 279 4443.98N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFIEYLIEGGPSSG- NH₂ 271 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2804115.66 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-EFIEYLIEGG-NH₂ 272 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 281 4327.914327.8 Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFIEYLIAGGPSSG- NH₂ 273 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 2823999.58 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQ-Aib-AFIEYLIAGG-NH₂ 274 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 283 4397.95N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQPAFIEYLIEGGPSSG- NH₂ 275 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 284 4069.63N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₆—CO₂H)AQPAFIEYLIEGG-NH₂ 276 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 285 4224.59 N/ILDEKAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH₂ 277Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 286 4224.55 N/I LDEQAQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂ 278 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 287 4327.74 N/ILDEKAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPSC-NH₂ 279Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- 288 4327.69 N/I LDEQAQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPSC-NH₂ 280 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 289 4210.61N/I Orn-KAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH₂ 281Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 290 4209.58 N/IOrn-QAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH₂ 282Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 291 4312.77 N/IOrn-KAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPSC-NH₂ 283Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- 292 4312.73 N/IOrn-QAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPSC-NH₂ 284Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 293 4208.64 N/ILD-Orn-KAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH₂ 285Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 294 4208.6 N/ILD-Orn-QAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH₂ 286Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 295 4311.78 N/ILD-Orn-KAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPSC-NH₂ 287Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- 296 4311.74 N/ILD-Orn-QAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPSC-NH₂ N/I means NotIncluded

Example 288Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH₂(SEQ ID NO:303)

The structure of SEQ ID NO:303 is depicted below using the standardsingle letter amino acid codes with the exception of residues Aib2, K17,Aib20, and Ser39, where the structures of these amino acid residues havebeen expanded:

The compound according to SEQ ID NO:303 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3 10=1602.5; Calc M+3=1602.8).

Example 289Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂(SEQ ID NO:304)

The structure of SEQ ID NO:304 is depicted below using the standardsingle letter amino acid codes with the exception of residues Aib2,αMeL13, K17, Aib20, and Ser39, where the structures of these amino acidresidues have been expanded:

The compound according to SEQ ID NO:304 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1626.8; Calc M+3=1626.8).

Example 290(D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂(SEQ ID NO:305)

The structure of SEQ ID NO:305 is depicted below using the standardsingle letter amino acid codes with the exception of residues D-Tyr1,Aib2, αMeL13, K17, Aib20, and Ser39, where the structures of these aminoacid residues have been expanded:

The compound according to SEQ ID NO:305 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1626.6; Calc M+3=1626.8).

Example 291(D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-AFI-(D-Glu)-YLIAGGPSSGAPPPS-NH₂(SEQ ID NO:306)

The structure of SEQ ID NO:306 is depicted below using the standardsingle letter amino acid codes with the exception of residues D-Tyr1,Aib2, αMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where thestructures of these amino acid residues have been expanded:

The compound according to SEQ ID NO:306 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1602.4; Calc M+3=1602.8).

Example 292(D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH₂(SEQ ID NO:307)

The structure of SEQ ID NO:307 is depicted below using the standardsingle letter amino acid codes with the exception of residues D-Tyr1,Aib2, αMeL13, K17, Aib20, αMeY25, and Ser39, where the structures ofthese amino acid residues have been expanded:

The compound according to SEQ ID NO:307 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1631.3; Calc M+3=1631.5).

Example 293(D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO—(CH₂)₁₈—CO₂H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH₂(SEQ ID NO:308)

The structure of SEQ ID NO:308 is depicted below using the standardsingle letter amino acid codes with the exception of residues D-Tyr1,Aib2, αMeL13, Orn16, K17, Aib20, αMeY25, and Ser39, where the structuresof these amino acid residues have been expanded:

The compound according to SEQ ID NO:308 is prepared substantially asdescribed by the procedures of Example 1. The molecular weight isdetermined by LC-MS (obsd: M+3=1626.5; Calc M+3=1626.8).

Example 294 Through Example 381

The compounds according to Examples 294 (SEQ ID NO:309) through Example381 (SEQ ID NO:396) are prepared substantially as described by theprocedures of Example 1.

Cal- culated Found Ex- SEQ MW MW am- ID (aver- (aver- ple Compound NameNO age) age) 294 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 309 4100.6 N/IAmino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQQAFIEYLIEGG-NH₂ 295 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 3104109.7 N/I Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQHAFIEYLIEGG-NH₂ 296 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 3114429.0 N/I Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQKAFIEYLIEGGPSSG- NH₂ 297 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-312 4057.6 N/I Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFIEYLIAGG-NH₂ 298 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-313 4313.9 N/I Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- AFVEYLIEGGPSSG-NH₂ 299Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 314 4385.9 N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO- (CH₂)₁₆-CO₂H)AQ-Aib- AFLEYLIEGGPSSG-NH₂ 300Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 315 4400.0 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIEGGPSSG-NH₂ 301 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 316 4400.04399.2 (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- AFIEYLIEGGPSSG-NH₂ 302 Y-Aib-EGT-αMeF(2F)- 3174418.0 N/I TSDYSILLDKK((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- AFIEYLIEGGPSSG-NH₂ 303Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 318 4400.9 4400.7(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIEGGPSSG-NH₂ 304 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 319 4458.0 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFIEYLIEGGPSSG-NH₂ 305 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 320 4341.9 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIAGGPSSG-NH₂ 306 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 321 4400.0 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFIEYLIAGGPSSG-NH₂ 307 Y-Aib-EGT-αMeF-TSDYSILLDEK((2-[2- 322 4400.9 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIEGGPSSG-NH₂ 308 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 323 4458.0 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFIEYLIEGGPSSG-NH₂ 309 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 324 4341.9 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIAGGPSSG-NH₂ 310 Y-Aib-EGT-αMeF- 325 4400.0 N/ITSDYSILLDKK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- EFIEYLIAGGPSSG-NH₂ 311 Y-Aib-EGT-αMeF(2F)- 3264418.9 N/I TSDYSILLDEK((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- AFIEYLIEGGPSSG-NH₂ 312 Y-Aib-EGT-αMeF(2F)-327 4476.0 N/I TSDYSILLDKK((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- EFIEYLIEGGPSSG-NH₂ 313 Y-Aib-EGT-αMeF(2F)-328 4359.9 N/I TSDYSILLDKK((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- AFIEYLIAGGPSSG-NH₂ 314 Y-Aib-EGT-αMeF(2F)-329 4418.0 N/I TSDYSILLDKK((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- EFIEYLIAGGPSSG-NH₂ 315Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 330 4835.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 316 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 331 4777.44777.2 Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH₂ 317 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 332 4356.0N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFIEYLIAGGPSSG-NH₂ 318 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 333 4414.0 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIAGGPSSG-NH₂ 319 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 334 4863.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 320 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 335 4430.0N/I Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-DFIEYLIEGGPSSG-NH₂ 321 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 336 4416.0 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-TFIEYLIEGGPSSG-NH₂ 322 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 337 4452.0 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-HFIEYLIEGGPSSG-NH₂ 323 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 338 4850.4 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 324 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 339 4819.5N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH₂ 325 Y-Aib-EGT-αMeF(2F)- 340 4895.5 N/ITSDYSILLDKK((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 326F-Aib-EGTFTSDYSILLDKK((2-[2-(2- 341 4847.5 N/IAmino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFIEYLIEGGPSSGAPPPS-NH₂ 327 F-Aib-EGTFTSDYSI- 342 4861.5 N/IαMeL-LDKK((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 328 F-Aib-EGTFTSDYSI-343 4847.5 N/I αMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIEYLIEAGPSSGAPPPS-NH₂ 329 (D-Tyr)-Aib-EGT-αMeF- 344 4877.5 N/ITSDYSILLDKK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 330 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2-345 4806.4 4805.4 Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH₂ 331Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 346 4878.5 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 332 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 347 4820.4N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH₂ 333 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 348 4935.6N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIEGGPSSGAPPPS-NH₂ 334 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 349 4877.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 335(D-Tyr)-Aib-EGT-αMeF-TSDYSI-αMeL- 350 4891.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 336(D-Tyr)-Aib-EGT-αMeF(2F)-TSDYSI- 351 4909.5 N/IαMeL-LDKK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH₂ 337 F-Aib-EGTFTSDYSI- 352 4803.5N/I αMeL-LDKK((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH₂ 338F-Aib-EGTFTSDYSI- 353 4861.5 N/I αMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 339 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 354 4732.44732.2 (2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 340 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 355 4819.54818.8 LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ- Aib-AFIEYLIAGGPSSGAPPPS-NH₂ 341(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 356 4820.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ- Aib-AFIEYLIAGGPSSGAPPPS-NH₂ 342(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 357 4878.5 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ- Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 343Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 358 4820.4 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFI-(D-Glu)- YLIAGGPSSGAPPPS-NH₂ 344Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 359 4864.4 N/I(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)- CO-(CH₂)₁₈-CO₂H)AQ-Aib-DFIEYLIAGGPSSGAPPPS-NH₂ 345 (D-Tyr)-Aib-EGT-αMeF-TSDYSI-αMeL- 360 4891.6N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ- Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 346(D-Tyr)-Aib-EGTFTSDYSI- 361 4805.5 4804.8 αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH₂ 347 (D-Tyr)-Aib-EGTFTSDYSI- 362 4791.4 N/IαMeL-LD-Dab-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH₂ 348(D-Tyr)-Aib-EGTFTSDYSI- 363 4807.5 N/I αMeL-LD-Dap-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH₂ 349 (D-Tyr)-Aib-EGTFTSDYSI- 364 4863.5 4862.7αMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH₂ 350(D-Tyr)-Aib-EGTFTSDYSI- 365 4849.5 N/I αMeL-LD-Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 351 (D-Tyr)-Aib-EGTFTSDYSI- 366 4835.5 N/IαMeL-LD-Dap-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH₂ 352(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 367 4819.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFI-(D-Glu)- YLIAGGPSSGAPPPS-NH₂ 353(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 368 4935.6 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH₂ 354 (D-Tyr)-Aib-EGTFTSDYSI-369 4863.5 N/I αMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈- CO₂H)AQ-Aib-EFI-(D- Glu)-YLIAGGPSSGAPPPS-NH₂ 355(D-Tyr)-Aib-EGTFTSDYSI- 370 4921.5 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈- CO₂H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂ 356 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 371 4877.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂ 357 (D-Tyr)-Aib-EGTFTSDYSI-372 4863.5 N/I αMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈- CO₂H)AQ-Aib-AFI-(D- Glu)-YLIEGGPSSGAPPPS-NH₂ 358(D-Tyr)-Aib-EGTFTSDYSI- 373 4791.4 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFVEYLIAGGPSSGAPPPS-NH₂ 359 (D-Tyr)-Aib-EGTFTSDYSI- 374 4849.5 N/IαMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- EFVEYLIAGGPSSGAPPPS-NH₂ 360(D-Tyr)-Aib-EGTFTSDYSI- 375 4849.5 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFVEYLIEGGPSSGAPPPS-NH₂ 361 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 376 4805.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFV-(D-Glu)-YLIAGGPSSGAPPPS-NH₂ 362 (D-Tyr)-Aib-EGTFTSDYSI-377 4791.4 N/I αMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFV- (D-Glu)-YLIAGGPSSGAPPPS-NH₂ 363(D-Tyr)-Aib-EGTFTSDYSI- 378 4777.4 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (D-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFI-Glu)-YLIAGGPSSGAPPPS-NH₂ 364 (D-Tyr)-Aib-EGTFTSDYSI- 379 4763.4 N/IαMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFV- (D-Glu)-YLIAGGPSSGAPPPS-NH₂ 365(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 380 4833.5 4832.4LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 366(D-Tyr)-Aib-EGTFTSDYSI- 381 4819.5 4818.3 αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-AFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 367 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2[2- 382 4891.6N/I (2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIE-αMeY- LIAGGPSSGAPPPS-NH₂ 368(D-Tyr)-Aib-EGTFTSDYSI- 383 4835.5 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH₂ 369 (D-Tyr)-Aib-EGTFTSDYSI- 384 4849.5 N/IαMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- DFIEYLIAGGPSSGAPPPS-NH₂ 370(D-Tyr)-Aib-EGTFTSDYSI- 385 4414.0 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (c-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIEYLIAGGPSSG-NH₂ 371 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 386 4718.3 N/ILD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH₂ 372(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 387 4746.4 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- EFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 373(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 388 4688.3 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 374(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 389 4863.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- EFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 375(D-Tyr)-Aib-EGTFTSDYSI- 390 4849.5 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 376 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 391 4805.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib- AFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 377(D-Tyr)-Aib-EGTFTSDYSI- 392 4791.4 4790.7 αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-AFIE-αMeY-LIAGGPSSGAPPPS-NH₂ 378 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 393 4732.4 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH₂ 379(D-Tyr)-Aib-EGTFTSDYSI-αMeL- 394 4949.5 N/ILDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- EFIE-αMeY-LIEGGPSSGAPPPS-NH₂ 380(D-Tyr)-Aib-EGTFTSDYSI- 395 4935.5 N/I αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂- (γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFIE-αMeY-LIEGGPSSGAPPPS-NH₂ 381 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 396 4934.4 N/ILDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib- AFIE-αMeY-LIAGGPSSGAPPPS-NH₂ N/I means Not Included

Binding Assays

Glucagon (referred to as Gcg) is a Reference Standard prepared at EliLilly and Company. GLP-1, 7-36-NH₂ (referred to as GLP-1) is obtainedfrom CPC Scientific (Sunnyvale, Calif., 97.2% purity, 100 μM aliquots in100% DMSO). GIP 1-42 (referred to as GIP) is prepared at Lilly ResearchLaboratories using peptide synthesis and HPLC chromatography asdescribed above (>80% purity, 100 μM aliquots in 100% DMSO).[¹²⁵I]-radiolabeled Gcg, GLP-1, or GIP is prepared using[¹²⁵I]-lactoperoxidase and obtained from Perkin Elmer (Boston, Mass.).

Stably transfected cell lines are prepared by subcloning receptor cDNAinto a pcDNA3 expression plasmid and transfected into human embryonickidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese Hamster Ovary (CHO)(hGIPR) cells followed by selection with Geneticin (hGLP-1R and hGIPR)or hygromycin B (hGcgR).

Two methods are used for the preparation of crude cell membranes.

Method 1:

Frozen cell pellets are lysed on ice in hypotonic buffer containing 50mM Tris HCl, pH 7.5, and Roche Complete™ Protease Inhibitors with EDTA.The cell suspension is disrupted using a glass Potter-Elvehjemhomogenizer fitted with a Teflon® pestle for 25 strokes. The homogenateis centrifuged at 4° C. at 1100×g for 10 minutes. The supernatant iscollected and stored on ice while the pellets are resuspended inhomogenization buffer and rehomogenized as described above. Thehomogenate is centrifuged at 1100×g for 10 minutes. The secondsupernatant is combined with the first supernatant and centrifuged at35000×g for 1 hour at 4° C. The resulting membrane pellet is resuspendedin homogenization buffer containing protease inhibitors at approximately1 to 3 mg/mL, quick frozen in liquid nitrogen and stored as aliquots ina −80° C. freezer until use.

Method 2:

Frozen cell pellets are lysed on ice in hypotonic buffer containing 50mM Tris HCl, pH 7.5, 1 mM MgCl₂, Roche Complete™ EDTA-free ProteaseInhibitors and 25 units/ml DNAse I (Invitrogen). The cell suspension isdisrupted using a glass Potter-Elvehjem homogenizer fitted with aTeflon® pestle for 20 to 25 strokes. The homogenate is centrifuged at 4°C. at 1800×g for 15 minutes. The supernatant is collected and stored onice while the pellets are resuspended in homogenization buffer (withoutDNAse I) and rehomogenized as described above. The homogenate iscentrifuged at 1800×g for 15 minutes. The second supernatant is combinedwith the first supernatant and centrifuged an additional time at 1800×gfor 15 minutes. The overall supernatant is then centrifuged at 25000×gfor 30 minutes at 4° C. The resulting membrane pellet is resuspended inhomogenization buffer (without DNAse I) containing protease inhibitorsat approximately 1 to 3 mg/mL and stored as aliquots in a −80° C.freezer until use.

Binding Determination Methods

The equilibrium binding dissociation constants (K_(d)) for the variousreceptor/radioligand interactions are determined from homologouscompetition binding analysis instead of saturation binding due to highpropanol content in the [¹²⁵I] stock material. The K_(d) valuesdetermined for the receptor preparations were as follows: hGcgR (3.9nM), hGLP-1R (1.2 nM) and hGIPR (0.14 nM).

[¹²⁵I]-Glucagon Binding

The human Gcg receptor binding assays are performed using aScintillation Proximity Assay (SPA) format with wheat germ agglutinin(WGA) beads (Perkin Elmer). The binding buffer contains 25 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4, 2.5mM CaCl₂, 1 mM MgCl₂, 0.1% (w/v) bacitracin (Research Products), 0.003%(w/v) Polyoxyethylenesorbitan monolaurate (TWEEN®-20), and RocheComplete™ Protease Inhibitors without EDTA. Peptides and Gcg are thawedand 3-fold serially diluted in 100%/DMSO (10 point concentrationresponse curves). Next, 5 μL serially diluted compound or DMSO istransferred into Corning® 3632 clear bottom assay plates containing 45μL assay binding buffer or unlabeled Gcg control (non-specific bindingor NSB, at 1 μM final). Then, 50 μL [¹²⁵I]-Gcg (0.15 nM final), 50 μLhuman GcgR membranes (1.5 μg/well) and 50 μL of WGA SPA beads (80 to 150μg/well) are added with a Biotek Multiflo dispenser. Plates are sealedand mixed on a plate shaker (setting 6) for 1 minute and read with aPerkinElmer Trilux MicroBeta® scintillation counter after 12 hours ofincubation/settling time at room temperature. Final assay concentrationranges for peptides tested in response curves is typically 1150 nM to0.058 nM and for the control Gcg from 1000 nM to 0.05 nM.

[¹²⁵I]-GLP-1 Binding

The human GLP-1 receptor binding assay is performed using an SPA formatwith WGA beads. The binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mMCaCl₂, 1 mM MgCl₂, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN®-20, andRoche Complete™ Protease Inhibitors without EDTA. Peptides and GLP-1 arethawed and 3-fold serially diluted in 100% DMSO (10 point concentrationresponse curves). Next, 5 μL serially diluted compound or DMSO istransferred into Corning® 3632 clear bottom assay plates containing 45μL assay binding buffer or unlabeled GLP-1 control (non-specific bindingor NSB, at 0.25 μM final). Then, 50 μL [¹²⁵I]-GLP-1 (0.15 nM final), 50μL human GLP-1R membranes (0.5 μg/well and 50 μL of WGA SPA beads (100to 150 μg/well) are added with a Biotek Multiflo dispenser. Plates aresealed and mixed on a plate shaker (setting 6) for 1 minute and readwith a PerkinElmer Trilux MicroBeta® scintillation counter after 5 to 12hours of incubation/settling time at room temperature. Final assayconcentration ranges for peptides tested in response curves aretypically 1150 nM to 0.058 nM and for the control GLP-1, 250 nM to 0.013nM.

[125I]-GIP Binding

The human GIP receptor binding assay is performed using an SPA formatwith WGA beads. The binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mMCaCl₂, 1 mM MgCl₂, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN®-20, andRoche Complete™ Protease Inhibitors without EDTA. Peptides and GIP arethawed and 3 fold serially diluted in 100% DMSO (10 point concentrationresponse curves). Next, 5 μL serially diluted compound or DMSO istransferred into Corning® 3632 clear bottom assay plates containing 45μL assay binding buffer or unlabeled GIP control (non-specific bindingor NSB, at 0.25 μM final). Then, 50 μL [¹²⁵I]-GIP (0.075-0.15 nM final),50 μL human GIPR membranes (3 μg/well) and 50 μL of WGA SPA beads (100to 150 μg/well) are added with a Biotek Multiflo dispenser. Plates aresealed and mixed on a plate shaker (setting 6) for 1 minute and readwith a PerkinElmer Trilux MicroBeta® scintillation counter after 2.5 to12 hours of incubation/settling time at room temperature. Final assayconcentration ranges for peptides tested in response curves is typically1150 to 0.058 nM or 115 nM to 0.0058 nM and for the control GIP, 250 nMto 0.013 nM.

Binding Assay Data Analysis

Raw CPM data for concentration curves of peptides, Gcg, GLP-1, or GIPare converted to percent inhibition by subtracting nonspecific binding(binding in the presence of excess unlabeled Gcg, GLP-1, or GIP,respectively) from the individual CPM values and dividing by the totalbinding signal, also corrected by subtracting nonspecific binding. Dataare analyzed using four-parameter (curve maximum, curve minimum, IC₅₀,Hill slope) nonlinear regression routines (Genedata Screener, version12.0.4, Genedata AG, Basal, Switzerland). The affinity constant (K_(i))is calculated from the absolute IC₅₀ value based upon the equationK_(i)=IC₅₀/(1+D/K_(d)) where D is the concentration of radioligand usedin the experiment, IC₅₀ is the concentration causing 50% inhibition ofbinding and K_(d) is the equilibrium binding dissociation constant ofthe radioligand (described above). Values for K_(i) are reported as thegeometric mean, with error expressed as the standard error of the mean(SEM) and n is equal to the number of independent replicates (determinedin assays performed on different days). Geometric Means are calculatedas follows:Geometric Mean=10^((Arithmetic Mean of Log Ki Values)))The Ki Ratio (Ki for native control peptide/Ki for test compound) ateach receptor and each species is calculated. The Ki Ratio is a rapidindication of the apparent affinity of a peptide compared to the nativecontrol peptide. A Ki Ratio <1 indicates that the test peptide has alower affinity (higher Ki value) for the receptor than the nativepeptide, whereas a Ki Ratio >1 indicates that the test peptide has ahigher affinity (lower Ki value) for the receptor than the nativepeptide.

n=1/x means that only one value out of the total number of replicates(x) is used to express the mean. SEM is only calculated when n=2 orgreater non-qualified results exist. Means are expressed as GeoMetricmeans with the standard error of the mean (SEM) and the number ofreplicates (n) indicated in parenthesis.

TABLE 1 In vitro Binding Affinity (K_(i)) of indicated Examples andcomparator molecules for human GLP-1R, GcgR and GIPR. Example hGLcgRhGIPR hGLP1R or com- Ki, nM Ki, nM Ki, (nM) parator (SEM, n) (SEM, n)(SEM, n) hGcg 3.65 (0.26, n = 10) hGIP 0.0922 amide (0.0085, n = 11)hGLP-1 0.614 amide (0.066, n = 12) 1 207 0.0546 6.67 (13.8, n = 5)(0.0120, n = 5) (1.25, n = 6) 2 361 0.0600 2.35 (55.1, n = 5) (0.0150, n= 5) (0.220, n = 5) 3 242 0.0458 2.23 (56.2, n = 6) (0.00357, n = 6)(0.366, n = 6) 4 686 0.0528 1.63 (n = ⅕) (0.00647, n = 5) (0.260, n = 5)5 519 0.0611 0.902 (109, n = 4) (0.00592, n = 4) (0.114, n = 4) 6 55.80.0835 6.71 (10.2, n = 2) (0.00437, n = 2) (1.25, n = 2) 7 198 0.25243.3 8 206 0.0772 2.84 (25.7, n = 2) (0.0155, n = 2) (0.753, n = 2) 9375 0.127 14.9 (87.5, n = 2) (0.0118, n = 2) (2.15, n = 2) 10 226 0.1099.33 (67.4, n = 2) (0.0927, n = 2) (1.49, n = 2) 11 174 0.226 15.7(25.3, n = 2) (0.0728, n = 2) (4.37, n = 2) 12 684 0.167 12.9 (141, n =2) (0.0853, n = 2) (2.71, n = 2) 13 >1060 0.296 31.1 (n = ½) (0.0291, n= 2) (11.9, n = 2) 14 160 0.0494 29.6 15 130 0.284 2.19 16 371 0.08412.78 17 261 0.606 7.63 (115, n = 2) (0.363, n = 2) (2.47, n = 2) 18 50.10.0798 0.319 19 60.5 0.0518 0.24 20 228 0.0849 3.30 (65.3, n = 2)(0.0168, n = 2) (1.01, n = 2) 21 149 0.529 14.5 22 53.4 0.624 23.123 >1010 0.258 6.32 24 49.8 0.232 5.04 25 81.1 0.179 4.8 26 >960 0.1764.22 27 315 0.103 3.68 28 >902 0.24 21.1 29 132 0.377 8 30 123 0.151 6.231 290 0.0275 6.58 32 44.7 0.0205 3.96 33 >979 6.4 361 34 134 0.04673.41 35 >964 0.0358 54.6 36 413 0.141 16.4 37 255 0.0523 3.84 38 >9740.104 31.3 39 161 0.0499 16.8 40 150 0.0345 7.56 41 165 0.0551 13.4 42160 0.0514 13.2 43 134 0.101 11.8 44 121 0.0516 10.6 45 11.1 0.0463 5.6546 133 0.0852 13.4 48 111 0.074 15.7 49 236 0.087 12.3 50 220 0.05684.71 (61.2, n = 2) (0.00744, n = 2) (1.22, n = 2) 51 195 0.0620 5.62(65.9, n = 2) (0.0131, n = 2) (0.658, n = 2) 52 >1100 0.0342 5.81 53 2160.188 1.23 54 333 0.965 1.66 55 >1100 6.24 7.29 56 >1060 0.148 10.3 5726.1 0.0583 3.00 (4.31, n = 2) (0.0131, n = 2) (0.293, n = 2) 58 3390.105 2.77 59 292 0.136 8.20 (11.8, n = 2) (0.00422, n = 2) (4.13, n =2) 60 237 0.0655 9.55 61 110 0.102 11.1 62 168 0.0545 2.03 63 273 0.1417.79 64 260 0.0866 4.86 65 194 0.0643 4.53 66 93.7 0.106 7.53 67 2700.061 10.2 68 99.2 0.0243 1.58 69 22.1 0.0300 1.22 (4.18, n = 3)(0.00657, n = 3) (0.353, n = 3) 74 69.8 0.0279 5.99 75 283 0.103 24.4 7614.4 0.0659 2.64 78 215 0.163 3.94 (66.2, n = 3) (0.0356, n = 2) (1.21,n = 2) 79 429 (n = ½) 0.0313 2.69 80 347 (n = ½) 0.0931 2.16 81 3440.198 2.88 82 >1060 14.9 6.82 83 320 0.142 7.1 84 >1100 0.143 10.285 >894(n = ½) 0.621 1.87 86 >1060 0.0401 3.74 87 278 0.0340 1.79 (n =½) (0.00150, n = 2) (0.417, n = 2) 88 545 0.0717 4.24 (57.8, n = 2) 89324 0.045 2.64 (22.9, n = 2) 90 245 0.0472 4.76 (7.55, n = 2) 91 540 1.85.23 93 15.7 0.0859 1.89 99 23.6 0.027 1.15 100 44 0.115 4.13 101 1170.0953 8.1 103 40.3 0.0645 6.68 104 123 0.0565 3.91 (17.1, n = 5)(0.0153, n = 5) (0.955, n = 5) 105 20.4 0.119 0.871 106 515 0.179 1.2107 303 0.0425 0.867 108 171 0.0732 3 109 43.1 0.0279 1.34 110 73.90.0395 4.38 115 9.89 0.0302 3.43 116 137 0.0597 6.80 (13.9, n = 2)(0.0486, n = 2) (1.85, n = 2) 117 192 0.0497 6.96 (14.6, n = 3) (0.0111,n = 3) (1.95, n = 3) 118 53.0 0.0859 6.10 (7.07, n = 3) (0.00402, n = 3)(0.870, n = 3) 119 30.6 0.0925 9.87 120 93.6 0.11 11.7 121 51.9 0.1773.16 122 43.3 0.190 3.36 (8.07, n = 2) (0.0189, n = 2) (0.799, n = 2)123 80.1 0.0469 1.31 (11.7, n = 6) (0.00804, n = 6) (0.197, n = 6) 12441.5 0.0424 4.87 (9.39, n = 2) (0.00200, n = 2) (0.277, n = 2) 125 54.40.0624 3.19 (0.365, n = 2) (0.0117, n = 2) (0.123, n = 2) 126 101 0.06441.46 (11.5, n = 2) (0.0267, n = 2) (0.299, n = 2) 127 43.6 0.126 1.86128 433 0.0625 1.88 (203, n = 2) (0.0355, n = 2) (0.296, n = 2) 129 14.90.0278 1 130 >1060 0.177 3.66 133 216 0.157 11.4 (2.31, n = 2) 134 60.50.14 12.7 (0.947, n = 2) 135 454 0.161 3.01 137 98.1 0.0373 1.24 (14.8,n = 3) (0.00200, n = 3) (0.341, n = 3) 138 61.2 0.0295 0.926 (4.65, n =2) (0.00145, n = 2) (0.201, n = 2) 139 105 0.0360 1.25 (6.68, n = 2)(0.00446, n = 2) (0.0904, n = 2) 140 175 0.0474 1.46 (40.1, n = 3)(0.00461, n = 3) (0.0630, n = 3) 142 53.1 0.0275 1.06 (1.60, n = 2)(0.00210, n = 2) (0.300, n = 2) 143 65.5 0.0304 1.15 144 77 0.0341 1.78145 158 0.0652 2.22 147 64.9 0.0981 4.47 (19.9, n = 2) (0.0285, n = 2)(0.742, n = 2) 149 127 0.0708 26.1 150 63.2 0.0649 30.5 152 93.4 0.11748 153 43.8 0.0578 22.2 154 762 0.0610 5.64 (51.7, n = 3) (0.00457, n =3) (2.52, n = 3) 157 179 0.0937 8.97 (82.9, n = 3) (0.0160, n = 3)(2.28, n = 3) 158 285 0.114 11.8 (17.4, n = 2) (0.0193, n = 2) (5.32, n= 2) 160 >1060 5.98 14.4 (n = ½) (1.46, n = 2) (3.72, n = 2) 163 1170.116 10.8 181 413 0.145 7.28 (132, n = 2) (0.0856, n = 2) (0.798, n =2) 182 565 0.0669 4.64 (335, n = 2) (0.0311, n = 2) (0.655, n = 2) 183304 0.0869 4.11 (128, n = 2) (0.0118, n = 2) (0.369, n = 2) 189 1460.128 8.81 (7.81, n = 2) (0.0817, n = 2) (0.434, n = 2) 191 348 0.1444.52 (54.7, n = 2) (0.0676, n = 2) (1.95, n = 2) 192 >1110 0.118 2.89 (n= ½) (0.108, n = 2) (0.516, n = 2) 202 394 0.0579 5.38 203 845 0.03373.90 (n = ½) (0.00260, n = 2) (1.10, n = 2) 204 >1150 0.0704 1.9 205 4380.0367 3.05 206 176 0.0814 5.27 (126, n = 2) (0.00608, n = 2) (0.359, n= 2) 207 74.2 0.0786 1.37 208 >1060 0.0537 2.13 209 >1060 0.0664 1.43 (n= ½) (0.0267, n = 2) (0.466, n = 2) 210 >1010 0.0399 1.58 211 131 0.02432.64 212 205 0.0978 2.76 (1.77, n = 2) (0.0730, n = 2) (0.561, n = 2)213 544 0.365 2.75 214 126 0.0304 1.99 215 75.2 0.0666 6.85 216 45.20.0559 2.34 217 516 0.0376 2.02 218 270 0.0593 2.54 219 373 0.0689 2.01220 377 0.0919 2.71 221 154 0.0414 1.77 (n = ½) (0.00291, n = 2) (0.900,n = 2) 222 71.3 0.0495 3.59 (11.9, n = 2) (0.0210, n = 2) (0.660, n = 2)223 46.5 0.0921 5.62 224 627 0.0482 6.86 (267, n = 2) (0.0174, n = 2)(1.85, n = 2) 225 714 0.0622 8.79 (n = ½) (0.0208, n = 2) (4.24, n = 2)226 200 0.0254 4.1 227 113 0.0146 2.01 228 182 0.028 2.43 229 >1100 2.4736.2 230 494 0.042 4.68 231 440 0.0394 3.03 232 >1150 0.0544 5.62233 >1150 0.0445 5.99 234 >1100 0.0563 10.9 235 >1200 0.0581 7.65 236200 0.0425 1.05 (15.1, n = 2) (0.00194, n = 2) (0.173, n = 2) 237 >10600.131 1.04 238 230 0.0403 0.548 239 596 0.101 2.71 (215, n = 3) (0.0172,n = 3) (0.0420, n = 3) 240 204 0.0284 0.552 241 167 0.0420 0.799 (45.6,n = 2) (0.0118, n = 2) (0.401, n = 2) 242 95.9 0.0604 0.853 (14.1, n =2) (0.00642, n = 2) (0.0475, n = 2) 243 145 0.0325 0.670 (5.05, n = 2)(0.00840, n = 2) (0.0478, n = 2) 244 87.8 0.0308 0.820 (2.39, n = 2)(0.0150, n = 2) (0.141, n = 2) 246 >1010 0.0509 0.812 (n = ⅓) (0.0147, n= 3) (0.0900, n = 3) 247 >1100 >55.1 4.39 248 >1050 0.0397 2.4 249 >10000.0394 2.35 250 198 0.0171 1.72 251 21.2 0.0249 1.09 252 26 0.009710.383 253 >912 0.138 2.57 254 148 0.108 2.58 255 257 0.0772 2.58 264 3880.015 0.412 265 567 0.0224 0.537 266 193 0.0666 2.01 (28.2, n = 2)(0.0189, n = 2) (0.256, n = 2) 267 349 0.0628 1.57 (178, n = 2)(0.00765, n = 2) (0.109, n = 2) 268 >1190 0.0814 3.98 269 >1100 0.1527.1 270 >1190 0.117 8.27 271 >1150 0.107 5.09 272 550 0.0353 1.22 (243,n = 2) (0.00276, n = 2) (0.291, n = 2) 273 724 0.0698 1.13 288 3450.0580 1.60 (35.7, n = 3) (0.0105, n = 3) (0.866, n = 3) 289 >10500.0457 2.63 (n = ⅓) (0.0220, n = 3) (1.74, n = 3) 290 308 0.0617 2.44 (n= ⅓) (0.0115, n = 3) (0.162, n = 3) 291 >872 0.129 3.16 (n = ½) (0.0346,n = 3) (0.270, n = 3) 292 595 0.0547 1.19 293 668 0.0775 1.64 294 6290.205 2.92 295 >1000 0.181 4.12 296 >1000 0.444 3.33 297 >1240 0.09582.98 298 >1370 0.0578 3.03 299 >1040 0.734 54.3 300 251 0.0504 2.13 30144.4 0.0273 0.875 (6.17, n = 3) (0.00127, n = 3) (0.0889, n = 3) 30218.5 0.0289 0.617 303 502 0.0580 3.69 (189, n = 3) (0.0151, n = 3)(1.86, n = 3) 304 >855 0.0499 4.44 305 352 0.0250 0.830 (30.8, n = 2)(0.00586, n = 2) (0.481, n = 2) 306 >1040 0.0349 2.86 307 117 0.0773 5.1308 94.2 0.0288 1.01 309 64.1 0.0264 1.04 310 174 0.0315 1.70 (8.97, n =2) (0.00162, n = 2) (0.144, n = 2) 311 115 0.0497 11.5 312 106 0.03481.63 313 27.6 0.0261 0.815 314 116 0.027 0.717 315 539 0.0677 2.28 316654 0.0418 0.957 (76.5, n = 3) (0.00224, n = 3) (0.180, n = 3) 317 2530.0215 2.63 318 730 (n = ½) 0.0452 7.52 (0.00883, n = 2) (0.256, n = 2)319 >984 0.0349 3.61 320 >1040 0.136 5.17 321 770 0.064 4.2 322 10300.175 2.31 323 300 0.0516 1.65 324 449 0.0278 0.609 325 13 0.0209 0.475326 207 0.251 2.92 327 114 0.0667 2.10 (8.53, n = 2) (0.0211, n = 2)(0.287, n = 2) 328 >1450 0.136 3.98 (n = ½) (0.0602, n = 2) (0.339, n =2) 329 17.0 0.0439 3.28 (2.51, n = 2) (0.0105, n = 2) (0.327, n = 2)330 >1050 0.114 12.7 331 >969 0.0851 11.4 (n = ½) (0.00508, n = 2)(0.160, n = 2) 332 397 0.0497 7.87 (272, n = 2) (0.00681, n = 2) (0.333,n = 2) 333 578 0.0634 4.25 (68.8, n = 2) (0.00255, n = 2) (0.180, n = 2)334 192 0.0646 2.17 335 27.1 0.0444 2.54 336 17.1 0.0277 2.44 337 3350.0363 1.61 338 >1060 0.0831 3.23 339 873 0.0388 2.69 (19.4, n = 2)(0.0198, n = 2) (0.218, n = 2) 340 250 0.0507 2.08 (60.8, n = 2)(0.0177, n = 2) (0.0742, n = 2) 341 39.7 0.0559 6.49 342 >1000 0.12915.4 343 >1070 0.0374 13.3 344 >1080 0.0507 14.8 346 310 0.0559 1.67(26.0, n = 3) (0.0248, n = 2) (0.911, n = 2) 349 >1060 0.0800 1.72 (n =⅓) (0.0215, n = 3) (0.0730, n = 3) 352 >1030 0.0726 3.03 (n = ½)(0.00687, n = 3) (0.673, n = 3) 354 >953 0.175 7.85 (0.0209, n = 2)(0.190, n = 2) 356 >1010 0.350 10.3 (0.0397, n = 2) (1.53, n = 2)357 >977 0.316 7.02 (0.0233, n = 2) (1.19, n = 2) 358 915 0.0636 1.37 (n= ½) (0.00684, n = 3) (0.189, n = 3) 359 >982 0.0874 2.59 (n = ½)(0.0159, n = 3) (0.833, n = 3) 360 485 0.128 1.74 (0.00895, n = 2)(0.0269, n = 2) 362 >1050 0.337 6.95 (0.00484, n = 2) (0.446, n = 2)363 >1020 0.170 3.89 (n = ½) (0.0113, n = 3) (0.864, n = 3) 364 >11500.672 17.2 (n = ½) (0.0431, n = 3) (2.26, n = 3) 367 777 0.0282 0.809Functional Activity (With BSA)

Functional activity is determined in hGLP-1R, hGcgR and hGIP-Rexpressing HEK-293 clonal cell lines. Each receptor over-expressing cellline is treated with peptide (20 point CRC, 2.75-fold Labcyte Echodirect dilution) in DMEM (Gibco Cat #31053) supplemented with 1×GlutaMAX™ supplement (L-alanyl-L-glutamine dipeptide Gibco®), 0.25% FBS(Fetal Bovine Serum), 0.05% fraction V BSA (Bovine Serum Albumin), 250μM 3-isobutyl-1-methylxanthine (IBMX) and 20 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) in a 20 μlassay volume.

After 60-minute incubation at room temperature, the resulting increasein intracellular cAMP is quantitatively determined using the CisBio cAMPDynamic 2 homogeneous time-resolved fluorescence (HTRF) Assay Kit. ThecAMP levels within the cell are detected by adding the cAMP-d2 conjugatein cell lysis buffer followed by the antibody anti-cAMP-Eu³⁺-Cryptate,also in cell lysis buffer. The resulting competitive assay is incubatedfor at least 60 minutes at room temperature and then detected using aninstrument with excitation at 320 nm and emission at 665 nm and 620 nm.Envision units (emission at 665 nm/620 nm*10,000) are inverselyproportional to the amount of cAMP present and are converted to nM cAMPper well using a cAMP standard curve.

The amount of cAMP generated (nM) in each well is converted to a percentof the maximal response observed with either human GLP-1(7-36)NH₂, humanGcg, or human GIP(1-42)NH₂. A relative EC₅₀ value is derived bynon-linear regression analysis using the percent maximal response vs.the concentration of peptide added, fitted to a four-parameter logisticequation.

EC₅₀ determination of human GLP-1(7-36)NH₂ at human GLP-1R, human Gcg athuman GcgR, and human GIP(1-42)NH₂ at human GIP-R: the peptideconcentration ranges were 448 pM to 99.5 nM. EC₅₀ determination ofExamples at human GLP-1R, human GcgR, and human GIP-R: the peptideconcentration ranges are 51.5 fM to 11.4 μM.

TABLE 2 Functional cAMP Potency (EC₅₀) for Example and comparatorpeptides (hGcg, hGIP amide, and hGLP-1 amide) in the presence of FBS.Example or cAMP EC₅₀, nM (SEM, n) comparator GcgR GIPR GLP-1R hGcg0.0125 ± 0.0011 (n = 12) hGIP 0.0979 (0.0088, amide n = 12) hGLP-10.0424 (0.0043, amide n = 12) Example 1 >11400 (n = 1/9) 38.5 (20.2, n =12) 53.3 (21.4, n = 12) Example 2 >10900 (n = 1/12) 2.64 (0.696, n = 12)6.52 (1.76, n = 11) Example 3 >10900 (n = 1/7) 9.24 (2.23, n = 7) 19.4(7.02, n = 7) Example 4 >10900 (n = 1/5) 1.03 (0.181, n = 5) 2.02(0.596, n = 4) Example 5 >10900 1.98 1.61cAMP Pharmacological Functional Assay in Presence of Casein

An additional set of cAMP assays are conducted in HEK293 cellsexpressing the human GLP-1 receptor (GLP-1R), gastric inhibitory peptidereceptor (GIPR), Glucagon receptor (GcgR). Pharmacological activity ofthe hGLP1R/GIPR peptides are determined in HEK293 cells stablyexpressing the human GLP-1 receptor (GLP-1R), gastric inhibitory peptidereceptor (GIPR), or GLP-2 receptor (GLP-2R). Each receptorover-expressing cell line (20 μl) is treated with the test peptide inDMEM (Gibco Cat #31053) supplemented with 0.1% Casein (Sigma Cat#C4765), 250 μM IBMX, 1× GlutaMAX™ (Gibco Cat #35050), and 20 mM HEPES(HyClone Cat #SH30237.01) in a 20 μl assay volume. After 60 minuteincubation at room temperature, the resulting increase in intracellularcAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRFAssay Kit (62AM4PEJ). The Lysis buffer containing cAMP-d2 conjugate (20μl) and the antibody anti-cAMP-Eu3+-Cryptate (20 μl) are then added todetermine the cAMP level. After 1 h-incubation at room temperature, HTRFsignal is detected with an Envision 2104 plate reader (PerkinElmer).Fluorescent emission at 620 nm and at 665 nm is measured and the ratiobetween 620 nm and at 665 nm is calculated and then are converted to nMcAMP per well using a cAMP standard curve. Dose response curves ofcompounds are plotted as the percentage of stimulation normalized tominimum (buffer only) and maximum (maximum concentration of each controlligand) values and analyzed using a four parameter non-liner regressionfit with a variable slope (Genedata Screener 13). EC50 is theconcentration of compound causing half-maximal simulation in a doseresponse curve. A relative EC₅₀ value is derived by non-linearregression analysis using the percent maximal response vs. theconcentration of peptide added, fitted to a four-parameter logisticequation.

Using Homogeneous Time Resolved Fluorescence methods, assays areconducted to determine the intrinsic potency of Example and comparatormolecules performed in the presence of casein (instead of serum albumin)as a nonspecific blocker, which does not interact with the fatty acidmoieties of the analyzed molecules.

Intracellular cAMP levels are determined by extrapolation using astandard curve. Dose response curves of compounds are plotted as thepercentage of stimulation normalized to minimum (buffer only) andmaximum (maximum concentration of each control ligand) values andanalyzed using a four parameter non-linear regression fit with avariable slope (Genedata Screener 13). EC₅₀ is the concentration ofcompound causing half-maximal simulation in a dose response curve. Eachrelative EC50 value for the Geometric mean calculation is determinedfrom a curve fitting.

Concentration response curves of compounds are plotted as the percentageof stimulation normalized to minimum (buffer only) and maximum (maximumconcentration of each control ligand) values and analyzed using a fourparameter non-liner regression fit with a variable slope (GenedataScreener 13). EC50 is the concentration of compound causing half-maximalsimulation in a dose response curve.

-   The EC₅₀ summary statistics are computed as follows:-   Geometric mean:-   GM=10{circumflex over ( )}(arithmetic mean of log₁₀ transformed EC₅₀    values).-   The standard error of the mean is reported:-   SEM=geometric mean×(standard deviation of log₁₀ transformed EC₅₀    values/square root of the # of runs)×log_(e) of 10.-   The log transform accounts for the EC₅₀ values falling on a    multiplicative, rather than an arithmetic scale.

Each day, the assay is run, the test peptides are run plus the nativeligands GIP and GLP-1, buffer only as baseline (minimum) and the highestconcentration of the respective GIP and GLP-1 standard is used asmaximum for calculations. For illustration, as shown by Example 1, thetest peptide is tested in 8 runs of the assay. For avoidance of doubt,hGIP amide and hGLP-1 amide EC50 in Table 3 are illustrative ofgeometric mean values from a series of 18 assay values, and values willvary each day compared to the zero buffer. Accordingly, each Examplewill use the geometric mean of those values to normalize the Exampleassay runs.

TABLE 3 Functional activation of hGLP-1R, hGIPR, hGcgR in the presenceof 0.1% Casein. Exam- hGIPR ple cAMP hGLP1R or Rel hGIPR cAMP hGLP1RcAMP cAMP com- EC₅₀ nM EC₅₀ ratio Rel EC₅₀ nM EC₅₀ ratio parator (SEM,n) (SEM, n) (SEM, n) (SEM, n) hGIP 0.170 amide (0.012, n = 18) hGLP-10.0396 amide (0.0030, n = 16) 1 0.0356 4.65 0.0410 1.12 (0.00576,(0.514, (0.00720, (0.0949, n = 8) n = 8) n = 7) n = 7) 2 0.0339 5.890.0441 0.888 (0.00650, (1.10, n = 5) (0.00670, n = 5) (0.0993, n = 5) n= 5) 3 0.0411 4.51 0.0338 1.25 (0.00541, (0.355, n = 5) (0.00156, n = 4)(0.0916, n = 4) n = 5) 4 0.0272 5.95 0.0297 1.41 (0.00358, (0.466, n =6) (0.00319, n = 6) (0.241, n = 6) n = 6) 5 0.0309 6.27 0.0164 2.69(0.00402, (0.808, n = 5) (0.00219, n = 5) (0.547, n = 5) n = 5) 6 0.08992.09 0.374 0.185 (0.0196, (0.301, n = 2) (0.0100, n = 2) (0.00340, n =2) n = 2) 7 0.461 0.317 0.470 0.130 (0.0988, n = 2) (0.0215, n = 2) 80.0848 1.97 0.148 0.419 (0.00744, (0.170, n = 6) (0.00926, n = 6)(0.0352, n = 6) n = 6) 9 0.210 0.768 0.194 0.314 (0.0335, (0.122, n = 6)(0.0284, n = 6) (0.0384, n = 6) n = 6) 10 1.28 0.151 7.64 0.00912(0.270, (0.0416, n = 2) (0.786, n = 2) (0.000859, n = 2) n = 2) 11 0.4860.399 6.89 0.0111 (0.108, (0.114, n = 2) (2.68, n = 3) (0.00387, n = 2)n = 3) 12 0.300 0.659 1.15 0.0603 (0.0827, (0.221, n = 2) (0.00296, n =2) (0.000359, n = 2) n = 2) 13 1.05 0.180 5.39 0.0133 (0.236, (0.0272, n= 2) (1.35, n = 2) (0.00338, n = 2) n = 2) 14 0.284 0.545 1.87 0.0306(0.0828, (0.161, n = 2) (0.534, n = 2) (0.00519, n = 2) n = 2) 15 0.6130.273 0.0336 1.65 (0.141, (0.00678, (0.0000222, (0.0634, n = 2) n = 2) n= 2) n = 2) 16 0.975 0.157 0.0437 1.43 (0.241, (0.0401, n = 2) (0.00494,n = 4) (0.260, n = 3) n = 2) 17 5.81 0.0257 0.152 0.398 (0.758,(0.00368, n = 2) (0.0166, n = 2) (0.0260, n = 2) n = 2) 18 0.610 0.2750.0945 0.589 (0.200, (0.0204, n = 2) (0.00823, n = 2) (0.0732, n = 2) n= 2) 19 0.386 0.436 0.104 0.532 (0.0583, (0.0449, n = 2) (0.00342, n =2) (0.0375, n = 2) n = 2) 20 0.0556 2.81 0.117 0.577 (0.00518, (0.293, n= 5) (0.0121, n = 8) (0.0706, n = 8) n = 5) 21 0.0748 1.95 0.160 0.402(0.00682, (0.145, n = 8) (0.00495, n = 7) (0.0178, n = 7) n = 8) 220.0842 1.86 0.206 0.290 (0.0103, (0.109, n = 4) (0.0172, n = 5) (0.0233,n = 5) n = 4) 23 0.204 0.754 0.190 0.342 (0.0160, (0.0348, n = 5)(0.00766, n = 7) (0.0255, n = 7) n = 5) 24 0.762 0.228 13.0 0.00416(0.206, (0.0443, n = 2) (n = ½) (n = ½) n = 2) 25 0.230 0.636 0.3560.197 (0.0191, (0.0564, n = 6) (0.0415, n = 6) (0.0287, n = 6) n = 6) 260.251 0.585 0.293 0.238 (0.0264, (0.0531, n = 6) (0.0442, n = 5)(0.0309, n = 5) n = 6) 27 0.0789 1.90 0.557 0.123 (0.00792, (0.295, n =6) (0.0717, n = 5) (0.0102, n = 5) n = 6) 28 1.66 0.106 32.7 0.00166(0.257, (0.0238, n = 2) (n = ½) (n = ½) n = 2) 29 0.320 0.536 0.9990.0671 (0.0548, (0.0522, n = 2) (0.336, n = 2) (0.0283, n = 2) n = 2) 300.114 1.50 1.84 0.0331 (0.00650, (0.0246, n = 2) (0.280, n = 2)(0.00127, n = 2) n = 2) 31 0.388 0.456 0.891 0.0708 (0.0773, (0.121, n =2) (0.147, n = 2) (0.0192, n = 2) n = 2) 32 0.179 0.840 0.498 0.136(0.0200, (0.0750, n = 5) (0.0124, n = 5) (0.00728, n = 5) n = 5) 33 63.30.00222 251 0.000256 (6.65, (0.000125, (n = ½) (n = ½) n = 2) n = 2) 340.360 0.393 1.56 0.0392 (0.0200, (0.00105, n = 2) (0.132, n = 2)(0.00119, n = 2) n = 2) 35 0.0905 1.58 8.38 0.00728 (0.00717, (0.215, n= 2) (0.707, n = 2) (0.000221, n = 2) n = 2) 36 0.309 0.458 2.29 0.0268(0.0126, (0.00789, n = 2) (0.390, n = 2) (0.00309, n = 2) n = 2) 370.269 0.532 1.15 0.0533 (0.0546, (0.0765, n = 2) (0.216, n = 2)(0.00707, n = 2) n = 2) 38 0.147 0.967 2.82 0.0217 (0.0217, (0.0861, n =2) (0.0832, n = 2) (0.00181, n = 2) n = 2) 39 0.133 1.07 1.92 0.0323(0.0242, (0.132, n = 2) (0.447, n = 2) (0.00571, n = 2) n = 2) 40 0.1361.06 0.746 0.0801 (0.0164, (0.188, n = 2) (0.118, n = 2) (0.0105, n = 2)n = 2) 41 0.229 0.637 0.960 0.0637 (0.0451, (0.159, n = 2) (0.0203, n =2) (0.00478, n = 2) n = 2) 42 0.161 0.897 1.45 0.0471 (0.00967, (0.149,n = 2) (0.328, n = 2) (0.0107, n = 2) n = 2) 43 0.112 1.28 0.862 0.0777(0.0129, (0.0105, n = 2) (0.0963, n = 2) (0.00826, n = 2) n = 2) 440.128 1.11 0.752 0.0918 (0.0118, (0.0174, n = 2) (0.201, n = 2) (0.0245,n = 2) n = 2) 45 0.106 1.75 1.03 0.0569 (0.0158, (0.164, n = 2) (0.194,n = 2) (0.00591, n = 2) n = 2) 46 0.172 0.828 0.687 0.0969 (0.0231,(0.0222, n = 2) (0.0147, n = 2) (0.00159, n = 2) n = 2) 47 0.287 0.6540.702 0.0890 (0.0529, (0.0819, n = 2) (0.197, n = 2) (0.0310, n = 2) n =2) 48 0.168 0.863 0.691 0.0966 (0.0126, (0.156, n = 2) (0.0491, n = 2)(0.00733, n = 2) n = 2) 49 0.0868 1.69 0.597 0.112 (0.0288, (0.372, n =2) (0.0314, n = 2) (0.00642, n = 2) n = 2) 50 0.0794 1.96 0.0961 0.675(0.0104, (0.179, n = 5) (0.00519, n = 7) (0.0492, n = 7) n = 5) 510.0960 1.69 0.153 0.426 (0.0106, (0.201, n = 7) (0.0110, n = 7) (0.0376,n = 7) n = 7) 52 0.0997 1.40 0.132 0.514 (0.0119, (0.154, n = 6)(0.0143, n = 5) (0.0413, n = 5) n = 6) 53 0.628 0.287 0.0339 1.80(0.161, (0.0912, n = 2) (0.000266, n = 2) (0.190, n = 2) n = 2) 54 1.570.110 0.0242 2.55 (0.144, (0.0181, n = 2) (0.00711, n = 2) (0.456, n =2) n = 2) 55 5.45 <0.00159 0.0286 2.33 (n = ½) (0.000346, n = 2)(0.0282, n = 2) 56 0.167 1.02 0.136 0.491 (0.0132, (0.00567, n = 2)(0.00964, n = 2) (0.0347, n = 2) n = 2) 57 0.0849 1.74 0.0668 0.996(0.0107, (0.148, n = 6) (0.00654, n = 7) (0.0730, n = 7) n = 6) 58 0.2660.522 0.180 0.378 (0.0307, (0.0439, n = 5) (0.0151, n = 5) (0.0347, n =5) n = 5) 59 0.0922 1.54 0.0840 0.812 (0.0134, (0.186, n = 5) (0.00742,n = 5) (0.0816, n = 5) n = 5) 60 0.135 1.06 0.287 0.237 (0.0107,(0.0296, n = 2) (0.0377, n = 3) (0.0270, n = 3) n = 2) 61 0.0739 1.940.371 0.187 (0.0140, (0.158, n = 2) (0.0664, n = 3) (0.0341, n = 3) n =2) 62 0.0601 2.33 0.159 0.463 (0.00469, (0.234, n = 5) (0.0151, n = 5)(0.0644, n = 5) n = 5) 63 0.0925 1.58 0.190 0.386 (0.0106, (0.156, n =7) (0.0195, n = 5) (0.0466, n = 5) n = 7) 64 0.0916 1.57 0.172 0.429(0.0104, (0.192, n = 6) (0.0184, n = 5) (0.0598, n = 5) n = 6) 65 0.1431.04 0.289 0.233 (0.0264, (0.295, n = 2) (0.0215, n = 3) (0.0144, n = 3)n = 2) 66 0.0743 1.89 0.285 0.255 (0.00740, (0.209, n = 5) (0.0291, n =5) (0.0245, n = 5) n = 5) 67 0.0913 1.61 0.447 0.123 (0.00577, (0.0648,n = 2) (0.0958, n = 2) (0.0314, n = 2) n = 2) 68 0.0881 1.67 0.153 0.354(0.00725, (0.0990, n = 2) (0.0169, n = 2) (0.0550, n = 2) n = 2) 690.0712 2.73 0.0844 0.850 (0.0156, (0.431, n = 3) (0.00548, n = 4)(0.0870, n = 4) n = 4) 70 0.480 0.351 0.283 0.207 (0.0706, (0.0135, n =2) (0.0281, n = 3) (0.0330, n = 3) n = 2) 71 0.166 1.02 1.02 0.0604(0.0417, (0.0668, n = 2) (0.227, n = 3) (0.0170, n = 3) n = 2) 72 0.2520.715 0.906 0.0645 (0.0456, (0.251, n = 2) (0.127, n = 3) (0.0103, n =3) n = 2) 73 0.979 0.174 2.55 0.0225 (0.317, (0.0239, n = 2) (0.337, n =3) (0.00178, n = 3) n = 2) 74 0.0866 1.70 0.467 0.115 (0.00653, (0.166,n = 2) (0.00217, n = 2) (0.00580, n = 2) n = 2) 75 0.214 0.690 1.490.0359 (0.0234, (0.0905, n = 2) (0.00142, n = 2) (0.00168, n = 2) n = 2)76 0.124 1.24 0.125 0.630 (0.000853, (0.0255, n = 2) (0.00942, n = 2)(0.0992, n = 2) n = 2) 77 135 0.00102 >2000 <0.0000325 (22.8, (0.000331,(n = ½) (n = ½) n = 2) n = 2) 78 0.532 0.293 0.544 0.143 (0.120,(0.0571, n = 2) (0.0263, n = 2) (0.00495, n = 2) n = 2) 79 0.0732 2.112.02 0.0410 (0.0127, (0.305, n = 2) (0.562, n = 2) (0.0142, n = 2) n =2) 80 0.140 1.09 0.351 0.227 (0.0130, (0.0709, n = 2) (0.0522, n = 2)(0.0516, n = 2) n = 2) 81 0.428 0.373 1.29 0.0630 (0.0445, (0.0131, n =2) (0.00950, n = 2) (0.00192, n = 2) n = 2) 82 24.3 0.00679 26.1 0.00325(8.06, (0.00175, n = 2) (6.81, n = 2) (0.000941, n = 2) n = 2) 83 0.1820.804 0.387 0.166 (0.0176, (0.0637, n = 2) (0.0648, n = 2) (0.0265, n =2) n = 2) 84 0.0915 1.59 0.374 0.173 (0.00451, (0.0514, n = 2) (0.0762,n = 2) (0.0337, n = 2) n = 2) 85 1.67 0.111 0.0518 1.13 (0.143,(0.00296, n = 2) (0.00318, n = 2) (0.0246, n = 2) n = 2) 86 0.0452 3.290.271 0.243 (0.00765, (0.605, n = 2) (0.0756, n = 2) (0.0647, n = 2) n =2) 87 0.0945 1.1 0.0801 0.786 (0.0277, n = 2) 88 0.475 0.392 0.6400.0918 (0.00187, (0.0215, n = 2) (0.00544, n = 2) (0.00840, n = 2) n =2) 89 0.119 1.57 0.335 0.175 (0.0150, (0.107, n = 2) (0.00771, n = 2)(0.0105, n = 2) n = 2) 90 0.0361 5.17 0.532 0.110 (0.000915, (0.434, n =2) (0.0564, n = 2) (0.00250, n = 2) n = 2) 91 19.2 0.0103 >5000<0.0000108 (n = ½) (n = ½) (n = ½) (n = ½) 92 0.338 0.546 0.257 0.258 930.185 0.956 0.115 0.498 (0.0241, (0.292, n = 2) (0.0143, n = 3) (0.0199,n = 3) n = 2) 94 0.425 0.434 0.338 0.196 95 1.17 0.145 1.01 0.0576(0.0326, (0.0227, n = 2) (0.229, n = 3) (0.00824, n = 3) n = 2) 96 0.7120.238 0.590 0.0977 (0.0736, (0.0195, n = 2) (0.0509, n = 3) (0.0101, n =3) n = 2) 97 1.85 0.0953 2.18 0.0268 (0.214, (0.0278, n = 2) (0.347, n =3) (0.00442, n = 3) n = 2) 98 0.0718 2.43 0.157 0.384 99 0.0643 2.270.0986 0.629 (0.0120, (0.208, n = 5) (0.0104, n = 4) (0.0938, n = 4) n =5) 100 0.120 1.48 0.0790 0.724 (0.0169, (0.191, n = 2) (0.00439, n = 2)(0.0809, n = 2) n = 2) 101 0.0704 2.07 0.0579 1.06 (0.00913, (0.138, n =5) (0.00589, n = 4) (0.131, n = 4) n = 5) 102 0.178 0.983 0.0628 0.913(0.00458, n = 2) (0.118, n = 2) 103 0.0693 2.01 0.101 0.655 (0.0165,(0.183, n = 4) (0.0132, n = 3) (0.108, n = 3) n = 4) 104 0.0323 4.930.0248 1.85 (0.00474, (0.595, n = 8) (0.00679, n = 6) (0.242, n = 6) n =8) 105 1.85 0.101 0.0401 1.51 (0.133, (0.00134, n = 2) (0.00740, n = 2)(0.396, n = 2) n = 2) 106 6.54 0.0302 0.0413 1.42 (n = ½) (n = ½)(0.000823, n = 2) (0.0898, n = 2) 107 0.241 0.747 0.0539 1.10 (0.0209,(0.0859, n = 5) (0.00678, n = 5) (0.128, n = 5) n = 5) 108 0.0885 2.190.294 0.218 (0.00413, (0.0798, n = 2) (0.0441, n = 2) (0.0253, n = 2) n= 2) 109 0.109 1.83 0.350 0.182 (0.0252, (0.397, n = 2) (0.0142, n = 2)(0.0134, n = 2) n = 2) 110 0.218 0.929 0.179 0.358 (0.0657, (0.263, n =2) (0.0168, n = 2) (0.0452, n = 2) n = 2) 111 0.141 1.1 0.308 0.209(0.0253, (0.0144, n = 2) (0.0151, n = 2) n = 2) 112 0.124 1.53 0.1600.402 (0.00217, (0.0115, n = 2) (0.0185, n = 2) n = 2) 113 0.166 1.390.233 0.275 (0.0364, (0.0133, n = 2) (0.0228, n = 2) n = 2) 114 0.1331.65 0.267 0.234 (0.0220, n = 2) 115 0.102 1.85 0.0880 0.743 (0.0163,(0.319, n = 5) (0.00660, n = 4) (0.0516, n = 4) n = 5) 116 0.0867 2.130.0703 0.956 (0.147, (0.0141, (0.255, n = 5) (0.0111, n = 4) n = 4) n =5) 117 0.0648 2.44 0.0615 0.998 (0.00602, (0.263, n = 6) (0.00275, n =7) (0.0681, n = 7) n = 7) 118 0.0538 3.42 0.0588 1.13 (0.00395, (0.247,n = 6) (0.00577, n = 6) (0.115, n = 6) n = 7) 119 0.216 0.901 0.09130.702 (0.0107, (0.0541, n = 2) (0.00729, n = 2) (0.0788, n = 2) n = 2)120 0.122 1.67 0.201 0.319 (0.0397, (0.509, n = 2) (0.0318, n = 2)(0.0398, n = 2) n = 2) 121 0.0760 1.44 0.0849 0.760 (0.0189, (0.0136, n= 2) (0.128, n = 2) n = 2) 122 0.0923 1.73 0.0760 0.856 (0.0122, (0.399,n = 2) (0.0221, n = 2) (0.223, n = 2) n = 2) 123 0.0423 4.04 0.0344 1.58(0.00604, (0.586, n = 8) (0.00562, n = 5) (0.180, n = 5) n = 8) 1240.0762 2.18 0.0475 1.29 (0.00816, (0.283, n = 4) (0.00318, n = 4)(0.0473, n = 4) n = 4) 125 0.0381 3.79 0.0478 1.31 (0.00482, (0.152, n =5) (0.00569, n = 4) (0.229, n = 4) n = 5) 126 0.0685 2.53 0.0715 0.869(0.00653, (0.361, n = 3) (0.00249, n = 4) (0.0332, n = 4) n = 4) 1270.158 0.917 0.145 0.443 (0.0401, (0.00951, n = 2) (0.0176, n = 2) n = 2)128 0.0694 2.46 0.0924 0.700 (0.00856, (0.344, n = 3) (0.0147, n = 4)(0.119, n = 4) n = 4) 129 0.106 1.88 0.121 0.543 (0.00707, (0.0220, n =2) (0.112, n = 2) n = 2) 130 1.55 0.116 0.368 0.182 131 0.183 1.03 0.1560.425 132 0.0657 2.88 0.26 0.255 133 0.0879 1.89 0.0436 1.52 (0.0298,(1.13, n = 2) n = 2) 134 0.104 1.43 0.0654 0.942 (0.00639, (0.244, n =2) (0.00394, n = 2) (0.00985, n = 2) n = 2) 135 0.373 0.482 0.131 0.509136 3.39 0.0544 0.06 1.1 137 0.0333 4.47 0.0397 1.25 (0.00461, (0.381, n= 8) (0.00540, n = 5) (0.114, n = 5) n = 8) 138 0.0581 2.18 0.0471 1.12(0.00498, (0.423, n = 3) (0.00784, n = 3) (0.105, n = 3) n = 3) 1390.0370 3.61 0.0417 1.13 (0.00460, (0.444, n = 5) (0.00760, n = 5)(0.105, n = 5) n = 5) 140 0.0349 3.76 0.0424 1.16 (0.00428, (0.415, n =5) (0.00487, n = 5) (0.0926, n = 5) n = 5) 141 0.2 0.538 0.0975 0.414142 0.0489 2.84 0.0426 1.22 (0.00436, (0.637, n = 2) (0.00626, n = 2)(0.0942, n = 2) n = 2) 143 0.0515 2.78 0.0745 0.714 (0.0105, (0.920, n =2) (0.0109, n = 2) (0.152, n = 2) n = 2) 144 0.0375 3.60 0.0608 0.851(0.00249, (0.373, n = 3) (0.00352, n = 3) (0.0845, n = 3) n = 3) 1450.0514 2.46 0.0427 1.22 (0.0124, (0.300, n = 3) (0.00108, n = 2) (0.116,n = 2) n = 3) 146 0.0583 1.98 0.0604 0.951 147 0.0304 4.14 0.0527 1.13(0.00146, (0.241, n = 3) (0.00623, n = 3) (0.117, n = 3) n = 3) 1480.0430 2.70 0.0626 0.859 (0.00713, (0.462, n = 3) (0.00751, n = 3)(0.167, n = 3) n = 3) 149 0.0711 1.82 0.0916 0.484 (0.0109, (0.0572, n =2) (0.0149, n = 2) (0.0343, n = 2) n = 2) 150 0.0511 2.64 0.0575 0.790(0.00569, (0.761, n = 2) (0.00855, n = 2) (0.186, n = 2) n = 2) 151 0.410.262 1.60 0.0278 (0.338, n = 2) (0.00331, n = 2) 152 0.0504 2.57 0.09150.484 (0.00566, (0.188, n = 2) (0.0128, n = 2) (0.0236, n = 2) n = 2)153 0.0634 1.7 0.0904 0.501 (0.0113, n = 2) (0.107, n = 2) 154 0.02665.90 0.0393 1.23 (0.00348, (0.513, n = 7) (0.00511, n = 5) (0.117, n =5) n = 7) 155 0.266 0.584 0.495 0.0978 156 >30.0 <0.00519 0.638 0.0759157 0.0453 3.15 0.0431 1.25 (0.00495, (0.444, n = 6) (0.00557, n = 4)(0.135, n = 4) n = 6) 158 0.0454 3.22 0.0374 1.34 (0.0102, (0.527, n =5) (0.00374, n = 5) (0.0947, n = 5) n = 5) 159 4.6 0.039 0.33 0.176 16021.0 0.00712 0.0461 1.24 (0.568, (0.00165, n = 2) (0.00206, n = 2)(0.0824, n = 2) n = 2) 161 0.254 0.706 4.8 0.0121 162 4.56 0.0393 360.00161 163 0.121 1.29 0.0316 1.54 164 3.09 0.0581 15.6 0.00373 165 1.040.172 5.81 0.01 166 0.355 0.504 4.08 0.0143 167 0.617 0.291 1.2 0.0487168 0.572 0.313 1.8 0.0323 169 0.86 0.122 3.37 0.0136 170 0.569 0.18510.4 0.00438 171 0.223 0.471 0.75 0.0609 172 1.05 0.1 1.2 0.038 1730.586 0.179 1.23 0.0373 174 0.217 0.483 0.472 0.0968 175 0.0881 1.191.11 0.0412 176 0.523 0.201 1.07 0.0427 177 1.4 0.0749 6.79 0.00673 1783.08 0.0341 13.1 0.00349 179 1.83 0.0575 2.7 0.0169 180 0.79 0.133 2.160.0212 181 0.0459 4.10 0.0592 0.718 (0.0122, (0.698, n = 5) (0.00966, n= 6) (0.0586, n = 6) n = 5) 182 0.0442 4.37 0.0463 0.873 (0.0133,(0.940, n = 5) (0.00578, n = 6) (0.0433, n = 6) n = 5) 183 0.0615 3.100.0551 0.843 (0.0175, (0.600, n = 5) (0.0125, n = 5) (0.121, n = 5) n =5) 184 0.0477 2.45 0.392 0.135 185 0.632 0.185 7.16 0.00739 186 0.09390.572 187 0.0371 4.61 0.0577 0.702 (0.00593, (0.839, n = 6) (0.00695, n= 6) (0.0431, n = 6) n = 6) 188 0.121 0.969 0.13 0.408 189 0.0775 2.410.0608 0.668 (0.0140, (0.314, n = 5) (0.00976, n = 6) (0.0450, n = 6) n= 5) 190 0.738 0.158 0.0241 2.2 191 0.0645 2.53 0.0356 1.60 (0.0139,(0.131, n = 3) (0.00490, n = 3) (0.182, n = 3) n = 3) 192 0.0615 2.830.0289 1.73 (0.0139, (0.340, n = 5) (0.00261, n = 5) (0.0510, n = 5) n =5) 193 0.336 0.538 0.162 0.359 194 0.423 0.427 0.284 0.205 195 0.1930.936 0.0966 0.602 196 0.277 0.653 0.175 0.332 197 0.211 0.855 0.2480.189 198 >30.0 <0.00602 0.139 0.337 199 >30.0 <0.00602 0.0422 1.11 20012.3 0.0146 0.0818 0.573 201 >30.0 <0.00602 0.0385 1.22 202 0.0392 4.790.0608 0.712 (0.00958, (0.700, n = 3) (0.00408, n = 2) (0.0866, n = 2) n= 3) 203 0.0387 4.95 0.0679 0.671 (0.00465, (0.383, n = 4) (0.0116, n =3) (0.130, n = 3) n = 4) 204 0.0424 4.58 0.0654 0.689 (0.0132, (1.01, n= 3) (0.0166, n = 2) (0.207, n = 2) n = 3) 205 0.0281 5.71 0.0261 1.46(0.000581, (0.519, n = 2) (0.00703, n = 3) (0.102, n = 3) n = 2) 2060.0409 4.75 0.0270 1.42 (0.00271, (0.0828, n = 2) (0.00477, n = 3)(0.139, n = 3) n = 2) 207 0.0395 4.76 0.0359 1.23 (0.0103, (0.715, n =3) (0.00622, n = 2) (0.275, n = 2) n = 3) 208 0.0371 5.33 0.0753 0.587(0.00797, (0.808, n = 4) (0.00608, n = 3) (0.0362, n = 3) n = 4) 2090.0308 5.73 0.0374 1.12 (0.00636, (0.721, n = 5) (0.00451, n = 4)(0.108, n = 4) n = 5) 210 0.0383 5.40 0.0432 1.03 (0.0124, (1.22, n = 4)(0.00554, n = 3) (0.118, n = 3) n = 4) 211 0.0442 4.59 0.0337 1.28(0.00939, (0.656, n = 5) (0.00481, n = 4) (0.203, n = 4) n = 5) 2120.0501 4.17 0.0572 0.771 (0.0132, (0.999, n = 4) (0.00467, n = 3)(0.0330, n = 3) n = 4) 213 0.0523 3.87 0.0710 0.694 (0.0140, (0.721, n =4) (0.0146, n = 4) (0.110, n = 4) n = 4) 214 0.0251 6.92 0.0221 1.74(0.00459, (0.628, n = 4) (0.00364, n = 5) (0.122, n = 5) n = 4) 2150.0525 3.53 0.0529 0.813 (0.00720, (0.379, n = 3) (0.00177, n = 2)(0.0175, n = 2) n = 3) 216 0.0401 4.91 0.0327 1.31 (0.0151, (1.22, n =3) (0.00291, n = 2) (0.0447, n = 2) n = 3) 217 0.0563 3.41 0.0383 1.14(0.0165, (0.665, n = 3) (0.00448, n = 2) (0.193, n = 2) n = 3) 2180.0413 4.43 0.0423 1.02 (0.00450, (0.113, n = 3) (0.00335, n = 2)(0.137, n = 2) n = 3) 219 0.0341 5.86 0.0403 1.03 (0.00595, (0.825, n =5) (0.00221, n = 4) (0.0601, n = 4) n = 5) 220 0.0315 6.30 0.0312 1.36(0.00564, (0.786, n = 5) (0.00267, n = 4) (0.176, n = 4) n = 5) 2210.0445 4.50 0.0570 0.795 (0.0102, (0.773, n = 4) (0.0101, n = 3) (0.138,n = 3) n = 4) 222 0.0306 5.84 0.0248 1.55 (0.00648, (0.924, n = 4)(0.00375, n = 5) (0.110, n = 5) n = 4) 223 0.0670 2.93 0.0363 0.962(0.00561, (0.487, n = 2) (0.00532, n = 3) (0.0435, n = 3) n = 2) 2240.0545 3.52 0.0349 1.06 (0.00995, (0.580, n = 3) (0.00788, n = 4)(0.145, n = 4) n = 3) 225 0.101 1.99 0.0670 0.523 (0.0194, (0.536, n =2) (0.0107, n = 3) (0.0355, n = 3) n = 2) 226 0.0461 4.27 0.0284 1.25(0.00446, (0.762, n = 2) (0.00805, n = 3) (0.167, n = 3) n = 2) 2270.0414 4.73 0.0329 1.07 (0.00954, (0.688, n = 2) (0.00627, n = 3)(0.0870, n = 3) n = 2) 228 0.0503 3.86 0.0282 1.10 (0.00265, (0.119, n =2) (0.00274, n = 2) (0.218, n = 2) n = 2) 229 4.79 0.0298 2.11 0.0139230 0.0431 3.31 0.0491 0.599 231 0.0253 5.64 0.0611 0.481 232 0.027 5.280.0724 0.406 233 0.0288 4.95 0.0549 0.535 234 0.0372 3.83 0.0926 0.317235 0.0372 3.83 0.136 0.216 236 0.0249 6.76 0.0231 1.65 (0.00475,(0.804, n = 5) (0.00333, n = 5) (0.260, n = 5) n = 5) 237 0.0883 2.160.0187 2.34 238 0.0296 7.33 0.0241 1.15 239 0.0353 5.27 0.0376 0.987(0.00282, (0.434, n = 4) (0.00836, n = 4) (0.213, n = 4) n = 4) 2400.0223 9.73 0.0393 0.706 241 0.0257 7.12 0.0175 1.89 (0.00164, (0.471, n= 3) (0.00373, n = 3) (0.340, n = 3) n = 3) 242 0.0333 5.58 0.0164 1.96(0.00196, (0.823, n = 3) (0.00209, n = 3) (0.186, n = 3) n = 3) 2430.0214 8.69 0.0265 1.22 (0.00212, (1.21, n = 3) (0.00423, n = 3) (0.158,n = 3) n = 3) 244 0.0225 8.27 0.0252 1.29 (0.00136, (1.30, n = 3)(0.00415, n = 3) (0.174, n = 3) n = 3) 245 0.0552 2.82 0.0222 1.55 2460.0258 6.36 0.0144 2.56 (0.00180, (0.340, n = 6) (0.00106, n = 5)(0.216, n = 5) n = 6) 247 0.0622 2.58 0.0491 0.614 248 0.0328 5.080.0428 0.800 (0.000561, (0.118, n = 2) (0.00493, n = 2) (0.00908, n = 2)n = 2) 249 0.0437 3.84 0.0446 0.778 (0.00337, (0.449, n = 2) (0.0131, n= 2) (0.129, n = 2) n = 2) 250 0.0376 4.27 0.0306 0.985 251 0.0292 5.120.081 1.37 252 0.093 1.61 0.0483 1.44 253 0.219 0.684 0.109 0.638 2540.215 0.695 0.0553 1.26 255 0.102 1.47 0.0407 1.71 256 0.643 0.2330.0506 1.38 257 0.474 0.316 0.0779 0.895 258 2.43 0.0616 0.174 0.401 2590.257 0.582 0.145 0.482 260 0.617 0.242 0.408 0.171 261 0.16 0.9360.0948 0.75 262 0.13 1.15 0.0943 0.754 263 0.317 0.473 0.0785 0.906 2640.0196 8.40 0.0229 3.19 (0.00197, (1.51, n = 2) (0.00180, n = 2) (0.327,n = 2) n = 2) 265 0.0229 7.56 0.0223 3.27 (0.00918, (2.21, n = 2)(0.00115, n = 2) (0.0894, n = 2) n = 2) 266 0.0442 2.82 0.0883 0.627(0.0109, (0.430, n = 6) (0.0104, n = 6) (0.103, n = 6) n = 6) 267 0.1081.50 0.0540 0.974 (0.0203, (0.0726, n = 5) (0.0118, n = 5) (0.256, n =5) n = 5) 268 0.239 0.851 0.0572 0.935 (0.00366, (0.0652, n = 3)(0.0135, n = 5) (0.247, n = 5) n = 3) 269 0.257 0.825 0.0595 0.828(0.0546, (0.187, n = 3) (0.0158, n = 3) (0.202, n = 3) n = 3) 270 0.3280.627 0.128 0.400 (0.0226, (0.0795, n = 3) (0.0355, n = 4) (0.132, n =4) n = 3) 271 0.334 0.614 0.0352 1.35 (0.0609, (0.0761, n = 3) (0.00104,n = 2) (0.0587, n = 2) n = 3) 272 0.0464 2.97 0.0435 1.19 (0.0119,(0.286, n = 6) (0.0117, n = 4) (0.355, n = 4) n = 6) 273 0.0790 2.150.0352 1.85 (0.0165, (0.333, n = 5) (0.0230, n = 3) (0.845, n = 3) n =5) 274 >30.0 <0.00741 14.5 0.00353 (5.14, n = 2) (0.000807, n = 2)275 >30.0 <0.00741 14.0 0.00357 (0.390, n = 2) (0.000336, n = 2) 2760.0757 1.43 0.108 0.491 (0.0236, n = 2) (0.117, n = 2) 277 0.0554 2.020.133 0.536 278 0.293 0.845 0.123 0.517 (0.0121, n = 2) (0.0592, n = 2)279 0.564 0.439 0.11 0.461 280 0.204 1.53 0.0767 0.663 281 0.166 1.870.16 0.318 282 0.323 0.962 0.247 0.23 283 0.301 1.03 0.155 0.329 2840.113 2.74 0.0462 1.1 285 0.0884 3.52 0.072 0.706 286 0.184 1.69 0.06020.845 287 0.15 2.08 0.112 0.455 288 0.0732 1.20 0.172 0.393 (0.0140,(0.268, n = 7) (0.0288, n = 4) (0.128, n = 4) n = 7) 289 0.0228 4.130.0544 1.33 (0.00219, (0.741, n = 5) (0.00661, n = 6) (0.325, n = 6) n =5) 290 0.0629 1.09 0.179 0.279 (0.0118, (0.176, n = 5) (0.0336, n = 6)(0.0844, n = 6) n = 5) 291 0.118 0.746 0.150 0.188 (0.0226, (0.0858, n =4) (0.0253, n = 5) (0.0294, n = 5) n = 4) 292 0.0682 1.10 0.183 0.143(0.0192, (0.0631, n = 2) (0.0328, n = 2) (0.0191, n = 2) n = 2) 2930.0562 1.36 0.132 0.197 (0.00736, (0.278, n = 2) (0.000967, n = 2)(0.00743, n = 2) n = 2) 294 0.183 0.75 0.185 0.249 295 0.281 0.481 0.1160.398 296 0.198 0.564 0.0867 0.82 297 0.0451 3.00 0.111 0.445 (0.00597,(0.569, n = 4) (0.0151, n = 5) (0.0482, n = 5) n = 4) 298 0.0430 2.870.0957 0.507 (0.00578, (0.349, n = 6) (0.0139, n = 7) (0.0734, n = 7) n= 6) 299 0.932 0.146 2.54 0.0244 (0.507, (0.0780, n = 2) (0.629, n = 4)(0.00551, n = 4) n = 2) 300 0.0234 5.38 0.0867 0.636 (0.00482, (1.40, n= 7) (0.0105, n = 9) (0.0568, n = 9) n = 7) 301 0.0346 4.11 0.0441 1.61(0.00764, (0.921, n = 11) (0.00684, n = 7) (0.433, n = 7) n = 12) 3020.0308 3.78 0.0275 1.96 (0.00225, (0.554, n = 7) (0.00247, n = 6)(0.175, n = 6) n = 8) 303 0.0254 4.20 0.104 0.602 (0.00381, (1.10, n =9) (0.0157, n = 6) (0.0702, n = 6) n = 9) 304 0.0296 2.68 0.191 0.481(0.00440, (0.425, n = 7) (0.0386, n = 5) (0.151, n = 5) n = 7) 3050.0225 4.28 0.107 0.685 (0.00306, (0.953, n = 7) (0.0149, n = 6)(0.0980, n = 6) n = 7) 306 0.0191 3.97 0.0711 0.912 (0.00502, (0.582, n= 4) (0.0202, n = 4) (0.339, n = 4) n = 4) 307 0.0285 2.48 0.0437 1.29(0.00345, (0.481, n = 5) (0.00943, n = 4) (0.238, n = 4) n = 5) 3080.0262 4.06 0.0392 1.45 (0.00432, (1.01, n = 8) (0.00818, n = 4) (0.307,n = 4) n = 8) 309 0.0389 1.64 0.0330 1.27 (0.00473, (0.313, n = 4)(0.00555, n = 3) (0.312, n = 3) n = 4) 310 0.0176 5.56 0.0283 1.43(0.00109, (1.23, n = 4) (0.00985, n = 3) (0.262, n = 3) n = 4) 3110.0334 3.50 0.0393 1.04 (0.00431, (0.928, n = 4) (0.0132, n = 3) (0.220,n = 3) n = 4) 312 0.0207 4.76 0.0262 1.53 (0.00251, (1.32, n = 5)(0.00799, n = 3) (0.342, n = 3) n = 5) 313 0.0233 2.87 0.0388 0.867(0.00223, (0.830, n = 2) (0.00647, n = 3) (0.197, n = 3) n = 2) 3140.0290 2.81 0.0290 1.48 (0.0123, (0.669, n = 2) (0.00867, n = 3) (0.476,n = 3) n = 2) 315 0.0408 2.06 0.0651 1.00 (0.00771, (0.452, n = 4)(0.0141, n = 4) (0.245, n = 4) n = 4) 316 0.0240 3.75 0.122 0.644(0.146, (0.00478, (0.723, n = 7) (0.00791, n = 6) n = 6) n = 7) 3170.0948 1.01 0.172 0.333 (0.0240, (0.478, n = 4) (0.00643, n = 3) (0.104,n = 3) n = 4) 318 0.0547 1.69 0.124 0.482 (0.00365, (0.536, n = 4)(0.0271, n = 4) (0.188, n = 4) n = 4) 319 0.0540 2.77 0.113 0.522(0.0220, (2.07, n = 4) (0.00689, n = 3) (0.171, n = 3) n = 4) 320 0.1610.241 0.397 0.224 321 0.0752 0.517 0.204 0.437 322 0.146 0.266 0.7110.125 323 0.0251 3.24 0.0597 1.32 (0.00551, (0.508, n = 4) (0.00797, n =4) (0.527, n = 4) n = 4) 324 0.0374 2.13 0.0926 0.798 (0.00637, (0.185,n = 4) (0.0147, n = 4) (0.264, n = 4) n = 4) 325 0.0301 2.65 0.0586 1.16(0.00366, (0.180, n = 5) (0.0119, n = 5) (0.224, n = 5) n = 5) 3260.0754 1.5 0.0369 1.4 327 0.0548 1.47 0.27 0.191 (0.0274, (0.273, n = ⅔)n = 2/3) 328 0.0965 0.94 0.117 0.575 329 0.132 0.687 0.125 0.535 3300.0919 0.562 0.199 0.255 331 0.0547 1.40 0.0929 0.808 (0.0162, (0.145, n= 2) (0.0237, n = 2) (0.277, n = 2) n = 2) 332 0.0745 0.949 0.184 0.345(0.0143, (0.0533, n = 3) (0.0348, n = 3) (0.0711, n = 3) n = 3) 3330.0492 2.31 0.131 0.487 334 0.0718 0.844 0.303 0.151 335 0.0477 1.270.122 0.374 336 0.0312 1.95 0.0874 0.523 337 0.0515 1.18 0.173 0.265 3380.0472 1.29 0.174 0.262 339 0.0219 3.18 0.0986 0.574 (0.00722, (0.768, n= 3) (0.0180, n = 4) (0.231, n = 4) n = 3) 340 0.0823 0.852 0.252 0.183(0.0288, (0.312, n = 3) (0.00594, n = 4) (0.0554, n = 4) n = 3) 3410.238 0.213 0.373 0.0674 342 0.159 0.32 0.127 0.198 343 0.0422 1.840.124 0.662 344 0.0433 1.79 0.044 1.86 345 0.0649 2.16 0.035 0.937 3460.144 0.604 0.128 0.210 (0.0284, (0.00648, n = 2) (0.0378, n = 3)(0.0493, n = 3) n = 2) 347 0.0827 0.872 0.102 0.245 (0.0247, n = 2)(0.0142, n = 2) 348 0.193 0.373 0.113 0.224 (0.00703, n = 2) (0.0269, n= 2) 349 0.117 0.756 0.121 0.214 (0.00129, (0.131, n = 2) (0.0287, n =3) (0.0378, n = 3) n = 2) 350 0.189 0.741 0.107 0.307 351 0.298 0.470.149 0.22 352 0.127 0.815 0.142 0.201 (0.0116, (0.193, n = 2) (0.0267,n = 3) (0.0439, n = 3) n = 2) 353 0.497 0.145 1.09 0.0231 (0.0881, n =2) (0.00235, n = 2) 354 0.233 0.441 0.540 0.0517 (0.0309, (0.0871, n =2) (0.126, n = 3) (0.00657, n = 2) n = 3) 355 0.685 0.111 0.896 0.0285(0.318, (0.0498, n = 2) (0.00185, n = 2) (0.00509, n = 2) n = 2) 3560.386 0.364 0.506 0.0647 357 0.384 0.366 0.181 0.181 358 0.183 0.6620.117 0.260 (0.0347, (0.0284, n = 2) (0.0257, n = 2) (0.0901, n = 2) n =2) 359 0.172 0.706 0.131 0.227 (0.0235, (0.00679, n = 2) (0.0201, n = 2)(0.0647, n = 2) n = 2) 360 0.197 0.53 0.145 0.171 361 0.401 0.261 0.9550.0259 362 0.302 0.347 0.365 0.0805 (n = ½) (n = ½) (0.0425, n = 2)(0.0202, n = 2) 363 0.145 0.835 0.208 0.146 (0.0185, (0.0159, n = 2)(0.0485, n = 2) (0.0522, n = 2) n = 2) 364 0.351 0.347 1.00 0.0303(0.0809, (0.0290, n = 2) (0.213, n = 2) (0.0103, n = 2) n = 2) 3650.0678 0.784 0.175 0.155 366 0.0889 0.598 0.366 0.074 367 0.0179 5.850.0641 0.386 368 0.0757 0.109 0.108 0.299 369 0.166 0.499 0.101 0.319370 0.117 0.704 0.186 0.172 371 0.135 0.393 0.132 0.206 372 0.0781 0.680.365 0.0741 373 0.185 0.287 0.436 0.0621 374 0.0468 1.76 0.190 0.169375 0.0471 1.13 0.152 0.178 376 0.0723 0.734 0.170 0.159 377 0.05440.976 0.136 0.199 378 0.067 0.793 0.191 0.142 379 0.079 0.672 0.2380.114 380 0.142 0.374 0.236 0.115As demonstrated by data in Table 3, Example compounds stimulate cAMPfrom human GLP-1R and GIPR in the presence of 0.1% casein.

In Vivo Studies

Pharmacokinetics in Male CD-1 Mice

The pharmacokinetics of select Examples are evaluated following a singlesubcutaneous administration of 200 nMol/kg to male CD-1 mice. Bloodsamples are collected over 168 hours and resulting individual plasmaconcentrations are used to calculate pharmacokinetic parameters. Plasma(K₃ EDTA) concentrations are determined using a qualified LC/MS methodthat measures the intact mass of the Examples. Each Example and ananalog as an internal standard are extracted from 100% mouse plasmausing immunoaffinity based precipitation with anti-GIP/GLP1 antibodies.Instruments are combined for LC/MS detection. Mean pharmacokineticparameters are shown in Table 4.

TABLE 4 Mean Pharmacokinetic Parameters of peptides Following a SingleSubcutaneous Administration of 200 nMol/kg to Male CD-1 mice (N =2/timepoint non-serial sampling). C_(max)/D AUCINF_D_obs Cl/F ExampleT_(1/2) (hr) T_(max) (hr) (kg * nmol/L/nmol) (hr * kg * nmol/L/nmol)(mL/hr/Kg) Example 1 17.54 12 4.84 135.61 7.37 Example 2 7.55 6 5.477.23 12.95 Example 3 15.04 6 4.42 158.49 6.31 Abbreviations: T_(1/2) =half-life, T_(max) = time to maximal concentration, C_(max) = maximalplasma concentration, AUCINF_D_obs = AUCinf divided by dose, CL/F =clearance/bioavailability. Notes: Data are the mean, where n =2/timepoint/group.Results from this study for Examples tested are consistent with anextended pharmacokinetic profile.Pharmacokinetics in Male Cynomolgus Monkeys

The pharmacokinetics of select Examples are evaluated following a singlesubcutaneous administration of 50 nMol/kg to male cynomolgus monkeys.Blood samples are collected over 336 hours and resulting individualplasma concentrations are used to calculate pharmacokinetic parameters.Peptide plasma (K₃ EDTA) concentrations are determined using a qualifiedLC/MS method that measured the intact mass of the compound. Each peptideand an analog as an internal standard are extracted from 100% cynomolgusmonkey plasma using immunoaffinity based precipitation withanti-GIP/GLG1 antibodies. Instruments are combined for LC/MS detection.Mean pharmacokinetic parameters are shown in Table 5.

TABLE 5 Mean Pharmacokinetic Parameters of peptides Following a SingleSubcutaneous Administration of 50 nMol/kg to Male Cynomolgus Monkeys.C_(max)/D AUCINF_D_obs Cl/F Example T_(1/2) (hr) T_(max) (hr) (kg *nmol/L/nmol) (hr * kg * nmol/L/nmol) (mL/hr/Kg) Example 1 125.0 18 6.51458 0.69 Example 2 102.1 24 11.7 2059 0.49 Example 3 180.6 30 11.383420 0.29 Abbreviations: T_(1/2) = half-life, T_(max) = time to maximalconcentration, C_(max) = maximal plasma concentration, AUCINF_D_obs =AUCinf divided by dose, CL/F = clearance/bioavailability. Notes: Dataare the mean, where n = 2/group. Notes: Data are the mean, where n =2/group. As seen in Table 5, results from this study for Examplepeptides tested are consistent with an extended pharmacokinetic profile.Pharmacokinetics in Male Sprague Dawley Rats Following Subcutaneous orIntrajejunal Administration

The pharmacokinetics of select Examples are evaluated following a singlesubcutaneous (SC) administration of 50 nMol/kg (dissolved in PBS, pH7.4) or single 1 μmol/kg (mixed with 250 mM sodium decanoate (“C10”) and12 mg/mL soybean trypsin inhibitor (SBTI)) intrajejunal (IJ)administration to male Sprague Dawley rats. Blood samples are collectedover 168 hours following SC administration and 72 hours following Udosing. Pharmacokinetic parameters are calculated using individualplasma concentrations. A qualified LC/MS method that measures the intactmass of the Example is used to determine plasma (K₃ EDTA)concentrations. Each Example is tested with an analog peptide as aninternal standard. Immunoaffinity based precipitation with anti-GIP/GLP1antibodies is used to extract each test peptide and analog. Meanpharmacokinetic parameters for the Examples are shown in Table 6 andTable 7.

TABLE 6 Mean (+/− SD) Pharmacokinetic Parameters of peptides Following aSingle Subcutaneous Administration of 50 nMol/kg to Male Sprague Dawleyrats. C_(max)/D AUCINF_D_obs Cl/F Example T_(1/2) (hr) T_(max) (hr)(kg * nmol/L/nmol) (hr * kg * nmol/L/nmol) (mL/hr/Kg) Example 1 44.7(6.2) 21.3 (4.6) 3.34 (0.22) 294.2 (30.0) 3.42 (0.33) Example 2 20.3(0.9) 14.7 (2.3) 5.19 (0.20) 231.7 (9.6)  4.32 (0.17) Example 3 32.1(1.9) 21.3 (4.6) 4.71 (0.50) 371.8 (21.8) 2.70 (0.16) Abbreviations:T_(1/2) = half-life, T_(max) = time to maximal concentration, C_(max) =maximal plasma concentration, AUCINF_D_obs = AUCinf divided by dose,CL/F = clearance/bioavailability. Notes: Data are the mean, where n =3/group (Table 6) As seen in table 6, results from this study usingthese Example peptides are consistent with an extended pharmacokineticprofile.

TABLE 7 Mean (+/− SD) Pharmacokinetic Parameters of peptides Following aSingle Intrajejunal Administration of 1 μmol/kg to Male Sprague Dawleyrats. C_(max)/D AUCINF_D_obs Example T_(max) (hr) (kg * nmol/L/nmol)(hr * kg * nmol/L/nmol) Example 1 1.33 (0.82) 0.08 (0.05) 1.31 (0.85)Example 2 0.25 (0.13) 0.56 (0.40) 6.6 (4.4) Example 3 0.33 (0)   0.47(0.16) 8.45 (3.1) 

Data are the mean, where n=3/group n=6/group (Table 7).

As illustrated by results in Table 7, these Examples are consistent withan exposure following intrajejunal administration. Intrajejunal exposurein this assay supports that the Examples may be suitable for oralformulation and administration.

In Vivo Effect on Insulin Secretion in Male Wistar Rats

Male Wistar rats with femoral artery and femoral vein canulas (Envigo,Indianapolis, Ind.) (280-320 grams) are single-housed in polycarbonatecages with filter tops. Rats maintained on a 12:12 h light-dark cycle(lights on at 6:00 A. M.) at 21° C. and receive food and deionized waterad libitum. Rats are randomized by body weight and dosed 1.5 ml/kg s.c.at doses of 0.04, 0.1, 0.3, 1, 3, and 10 nmol/kg 16 hours prior toglucose administration then fasted. Animals are weighed and anesthetizedwith sodium pentobarbital dosed i.p. (65 mg/kg, 30 mg/ml). A time 0blood sample is collected into EDTA tubes after which glucose isadministered i.v. (0.5 mg/kg, 5 ml/kg). Blood samples are collected forglucose and insulin levels at time 2, 4, 6, 10, 20 and 30 min postintravenous administration of glucose. Plasma glucose levels aredetermined using a clinical chemistry analyzer. Plasma insulin isdetermined using an electrochemiluminescence assay (Meso Scale,Gaithersburg, Md.). Glucose and insulin AUC are examined compared to thevehicle control with n=5 animals per group. Results are presented(SEM)(N).

TABLE 8 The effect of Example compounds on insulin secretion duringintravenous glucose tolerance test. Dose (nmol/kg, s.c.) Exam- ple 0.00.04 0.1 0.3 1.0 3 10 1 31.3 32.2 31.5 24.7 35.1 43.5 63.9 (2.8) (5.7)(4.5) (3.0) (4.0) (4.9) (6.5) (5) (5) (5) (5) (5) (5) (5) 2 18.9 32.849.1 82.2 110.9 108.2 77.3 (4.3) (3.9) (4.8) (21.1) (23.1) (20.2) (8.8)(5) (5) (5) (5) (5) (5) (5) 3 18.5 26.0 24.6 44.9 60.1 95.5 87.7 (1.0)(3.4) (3.9) (9.6) (4.0) (18.4) (7.9) (5) (5) (5) (5) (5) (5) (5) 4 33.734.0 42.0 86.3 90.2 108.7 114.6 (5.3, 5) (3.4, 5) (3.8, 5) (4.5, 5)(9.2, 5) (9.8, (16.1, 5) 5) 5 24.4 28.2 40.2 41.1 44.1 54.3 94.2 (3.0,5) (4.2, 5) (6.0, 5) (2.7, 5) (4.5, 5) (11.9, (10.1, 5) 5)

The data provided by Table 8 demonstrate a dose dependent increase ininsulin secretion.

TABLE 9 ivGTT Insulin Secretion shown by the following data: Insulinsecretion (ivGTT) Example (ED₅₀, nmol/kg) (SEM, n) 1 >10 2 0.1 (0.05, 5)3 0.7 (0.3, 5)  4 0.2 (0.05, 5) 5 3 < ED₅₀ < 10

The data provided by Table 9 demonstrate dose dependent increase ininsulin secretion.

Studies in Diet-Induced Obese C57/B16 Mice

C57/B16 diet-induced obese (DIO) male mice (Taconic, Germantown, N.Y.)weighing 41-50 g are used. Animals are individually housed in atemperature-controlled (24° C.) facility with a 12 hour light/darkphotoperiod (lights off at 10:00 A M and lights on at 10:00 PM), withfree access to food and water. After 2 week acclimatization to thefacility, mice are randomized to treatment groups (n=6/group) based onbody weight so each group has similar starting mean body weight.

Mice are treated with either vehicle (40 mM Tris-HCl at pH 8.0) orseveral peptides between the dose ranges of 0.03 nmol/kg to 10 nmol/kg.Treatments are subcutaneously administered to ad libitum fed DIO mice30-90 minutes prior to the onset of the dark cycle daily (QD) for 14days. During the course of the study, body weight and food intake aremonitored daily.

All data are expressed as mean±SEM of 5-6 rats per group. Statisticalanalyses are assessed by one-way ANOVA followed by Dunnett's multiplecomparison test to compare treatment groups to vehicle group or eachother. Significant differences are identified at p<0.05.

${{Percent}\mspace{14mu}{Body}\mspace{14mu}{Weight}} = {\frac{{Body}\mspace{14mu}{weight}\mspace{14mu}{after}\mspace{14mu} 14\text{-}{day}\mspace{14mu}{treatment}}{{Body}\mspace{14mu}{weight}\mspace{14mu}{before}\mspace{14mu}{treatment}\mspace{14mu}{started}} \times 100}$“0” dose group represents the vehicle-treated mice during each study.All data are expressed as mean±SEM of 5-6 mice per group. Statisticalanalyses are assessed by one-way ANOVA followed by Dunnett's multiplecomparison test to compare treatment groups to ‘0’ dose (vehicle).*Significant differences are identified at p<0.05. Body weight changeafter treatment with Example compounds after 15 days. “Δ from vehicle”refers to difference between body weight at day 15 between test andvehicle groups. “% change” refers to percent decrease in body weightbetween days 1 and 15 in test groups. Percent decrease in body weightfor animals receiving vehicle is recorded, and is less than about 1% ineach study. The A from vehicle and % change data are statisticallysignificantly different (p<0.05) than control for all Examples at alldoses tested.

TABLE 10 The effect of GIP/GLP-1 receptor co-agonists on percent bodyweight in diet-induced obese mice after 14-day of treatment. Dose(nmol/kg, s.c., QD) Peptide 0 0.03 0.1 0.3 1 3 10 Example 1  99.2 ± 0.8 96.2 ± 1.2 95.6 ± 0.9 86.7 ± 1.3* 86.3 ± 1.9* 74.0 ± 3.8* 64.7 ± 2.6*Example 2 100.5 ± 1.4 101.5 ± 0.2 95.0 ± 1.2 86.5 ± 0.8* 76.4 ± 4.0*76.4 ± 2.4* 68.1 ± 3.1* Example 3  98.0 ± 0.7  99.1 ± 1.3 95.6 ± 1.393.0 ± 1.1 85.6 ± 0.8* 75.9 ± 4.3* 73.6 ± 1.7* Example 4  98.3 ± 1.1 96.6 ± 0.5 94.7 ± 1.8 88.5 ± 1.2* 76.9 ± 1.4* 66.6 ± 3.9* 64.5 ± 2.2*Example 5  98.3 ± 1.1  96.0 ± 1.3 96.7 ± 1.1 94.1 ± 1.8 82.4 ± 1.6* 83.8± 1.6* 74.9 ± 2.3* Example 104  99.2 ± 0.8  94.0 ± 0.6 94.1 ± 0.8 89.0 ±0.9* 82.7 ± 1.5* 70.8 ± 4.2* 71.3 ± 4.1* Example 123  99.2 ± 0.8  94.7 ±0.9 90.5 ± 1.6* 86.5 ± 1.1* 81.3 ± 2.0* 75.1 ± 1.8* 68.6 ± 1.9*

As illustrated by data provided in Table 10 above, Example compoundstested in the assay dose-dependently reduce body weight in the studiesdescribed.

Proteolytic Stability Assay

The proteolytic stability assay is a useful for assessing potential fororal delivery of peptides. The stability of peptides are compared in 1%rat small intestinal fluid (rSIF). The amount of intact peptide ismeasured for a sample peptide at 0, 3, 15, and 30 minutes to assessproteolytic stability. The amount of intact peptide for a sample peptideis measured in 90% pig small intestinal fluid (pSIF) at 0, 30, 45, and60 minutes to assess the proteolytic stability.

Sample preparation when rat small intestinal fluid (rSIF) is used:

Peptides are prepared at 0.4 mg/mL in 50 mM Tris pH8.0. Rat smallintestinal fluid is added at a ratio of 1% (v/v). The mixture isincubated at 37° C. at 150 rpm. Thirty μL of each sample are removed andplaced into a new tube before the rSIF is added and at 3, 15, and 60min. At each time point, the reaction was quenched by 1% TFA in 50% ACNat 1:1. The samples are diluted 100 times using dilution buffer (1:1 of1% TFA in 50% ACN: 50 mM Tris pH8) and ready for analysis using massspectrometry (MS).

Sample preparation when pig small intestinal fluid (pSIF) is used:

Peptides are diluted to a concentration of 0.4 mg/mL in 90% pig smallintestinal fluid. After the mixing, 20 μL are immediately removed (time0 for the time point of pre-incubation). The mixture is then incubatedat 37° C. at 150 rpm. Twenty μL of each sample are removed and placedinto a new tube at 30, 45, and 60 min. At each time point (0, 30, 45,60), the reaction is quenched by 1% TFA in 50% ACN at 1:1. The sample iscentrifuged at 20,000×g for 20 min at 4° C. The supernatant is diluted100 times using dilution buffer (1:1 of 1% TFA in 50% ACN: 50 mM Tris pH8) and ready for analysis using mass spectrometry (MS).

MS Conditions: The liquid chromatography separation is carried out on aWaters Acquity UPLC using mobile phase A (0.1% formic acid in water) andB (0.1% formic acid in acetonitrile and an ACQUITY UPLC Protein BEH C4Column (300 Å, 1.7 μm, 1 mm×50 mm) at 40° C. The gradient is 5% of Bduring 0-1.5, 5-90% of B during 1.5-1.8, 90-95% of B during 1.8-3.0,95-95% of B during 3.0-3.5, 95-5% of B during 3.5-4.0, and 5-5% of Bduring 4.0-5.0. The MS analysis is carried out on a Waters Xevo G2-XSQTOF. The data is acquired using MSe Continuum in the range of 50-2000m/z in positive and sensitivity mode. The data analysis is performedusing MassLynx.

TABLE 11 The percentage of each peptide not cleaved at different timepoints using rSIF. 0 min 3 min 15 min 60 min Example 1 100 82.4 41.4 1.6Example 2 100 75.5 18.3 0.3 Example 3 100 68.8 25.8 0.3 Example 4 10097.9 99.3 89.4 Example 69 100 2.2 0.0 0.0The proteolytic peptide results provided in Table 11 suggest that thepeptide of Example 4 may be suitable for oral formulation and delivery.

TABLE 12 The percentage of each peptide not cleaved at different timepoints using pSIF. 0 min 30 min 45 min 60 min Example 4 100 73.4 56.460.0 Example 5 100 76.9 56.8 60.7

The proteolytic peptide results provided in Table 12 suggest that boththe peptides of Examples 4 and 5 may be suitable for oral formulationand delivery.

In Vivo Studies

The purpose of this study is to determine the relative potential forclinical immunogenicity of a compound.

Methods:

CD8+ T cell depleted peripheral blood mononuclear cells are prepared andlabeled with Carboxyfluorescein Diacetate Succinimidyl Ester (CFSE,Invitrogen) from a cohort of 10 healthy donors. Samples are tested intriplicate with 2.0 mL media control, keyhole limpet hemocyanin (“KLH”)(0.33 μM), anti-chemokine receptor type 4 (“CD4+”) (0.33 μM), and acompound of Examples 1, 2, and 3 (10 μM). Cultures are incubated for 7days at 37° C. with 5% CO₂. On day 7, samples are analyzed by flowcytometry using High Throughput Sampler (HTS). Data is analyzed usingFlowJo® Software (FlowJo, LLC, TreeStar).

Results and Discussion

All donors produce a positive T cell response against KLH (100%).Analysis of the frequency and magnitude of the CD4+ T cell response forExample compounds is shown in Table 13.

TABLE 13 CD4+ T Cell Responses for Example compounds and PositiveControl (KLH). Median Response Strength in % Donor Response positivedonors (CDI) KLH 100% (n = 11)    391 (n = 10) Example 1 (GG-212) 9% (n= 11)  0.7 (n = 1) Example 2 (GG-353) 22% (n = 9)  3.68 (n = 2) Example3 (GG-362) 0% (n = 9)  NA (n = 0) Example 4 (GG-427) 0% (n = 9)  NA (n =0) Example 288 (GG-709) 10% (n = 10)  5.42 (n = 1) Example 289 (GG-731)0% (n = 10) NA (n = 0) Example 301 (GG-650) 0% (n = 10) NA (n = 0)Example 303 (GG-679) 0% (n = 10) NA (n = 0) Example 316 (GG-698) 0% (n =10) NA (n = 0) Cell Division Index (“CDI”): proportion of divided CD4+ Tcells to the total number of CD4+ T cells in stimulated versusunstimulated samples.These data show that the frequency of positive CD+ T cell response(CDI>2.5) was low for the compounds of Examples 1, 2, 3, 4, 288, 289,301, 303 and 316, and the magnitude of the response in the few positivedonors was low (CDI<6), indicating a low risk of immunogenicity usingthe CD4+ T cell assay.GLP-1R HEK293 Cell Membrane [³⁵S]GTPγS Binding Assay

The GLP-1 receptor is a G-protein coupled receptor that increasesGTP-bound Gα_(s) upon ligand induced receptor activation. The potency ofpeptides to stimulate-GLP-1R induced activation of Gα_(s) is determinedusing preparations of purified membranes from HEK293 cells expressingthe human GLP-1R. The assay is performed similarly to that as previouslydescribed (Bueno et al., J. Biol. Chem., (2016) 291, 10700 and Willardet al., Mol. Pharmacol. (2012) 82, 1066). The test peptides aresolubilized in DMSO and diluted in reaction buffer containing 5 μg ofmembrane in 20 mM HEPES pH 7.4, 50 mM NaCl, 5 mM MgCl₂, 40 μg/mlsaponin, 0.1% BSA, and 500 pM ³⁵S-labeled GTPγS for 30 minutes at roomtemperature. Reactions are terminated by addition of 0.2% Nonidet P-40detergent containing rabbit anti-Gas polyclonal antibody and 0.5 mg ofanti-rabbit polyvinyltoluene beads. Mixtures are developed for 30minutes, centrifuged at 80×g for 10 minutes, and counted for 1minute/well using a MicroBeta TriLux instrument. Peptideconcentration-response curves are fit to a four-parameter logistic modelto calculate potency as an EC₅₀. Data normalization to % stimulation isperformed using DMSO and GLP-1(7-36) as minimum and maximum controls forthe receptor (Campbell et al, Assay Guidance Manual 2017). The potencyof a sample peptide to stimulate GIPR induced activation of Gα_(s) isreported in the Table 14. Assay results identify a peptide that is apartial agonist on the GLP-1R with respect to GLP-1R induced activationof Gα_(s).

GLP-1R CHO Cell β-Arrestin Recruitment Assay

Activated G-protein coupled receptors can interact with the β-arrestinfamily of signalling proteins. The potency of peptides for GLP-1Rinduced arrestin recruitment is determined using the PathHunter EnzymeFragment Complementation approach substantially as described (vonDegenfeld et al., FASEB J., 2007 (14):3819-26 and Hamdouchi et al., J.Med Chem., 2016 59(24): 10891-10916). CHO-K1 cells expressingPro-Link-tagged Human GLP-1R and enzyme-acceptor-tagged β-arrestin-2 maybe obtained from DiscoveRx and prepared as assay-ready frozen cells.Test peptides are solubilized in DMSO and serial dilutions are performedusing the Echo acoustic dispenser (LabCyte). Assay media is thePathHunter Cell Assay Buffer (DiscoveRx) containing 0.1% w/v hydrolyzedCasein (Sigma). 100 nl of peptide is dispensed into 10 μl of assay mediain a 384 well plate and then 10 μl of cells in assay media are added togive 5000 cells per well. Plates are incubated for 90 minutes in a37′C/5% C02 incubator and 10 μl of PathHunter detection reagent is added(DiscoveRx) and plates are incubated at room temperature for 60 minutes.Luminescence signal is measured. Peptide concentration-response curvesfit to a four-parameter logistic model to calculate potency as an EC₅₀.Data normalization to % stimulation is performed using DMSO andGLP-1(7-36) as minimum and maximum controls (Campbell et al, AssayGuidance Manual 2017). The potency of a sample peptide to stimulateGLP-1R induced β-arrestin recruitment is reported in Table 14. The assayresults identify a peptide that is a partial agonist on the GLP-1R withrespect to β-arrestin-2 recruitment.

TABLE 14 hGLP1R hGLP1R hGLP1R B- GTPgS Rel GTPgS % Arrestin2 Rel hGLP1RB- EC50 nM Top (SEM, EC50 uM Arrestin2% Example (SEM, n) n) (SEM, n) Top(SEM, n) 0.475 99.2 0.00274 104 (0.0322, (0.659, (0.000359, n = 42)(3.45, n = 42) n = 115) n = 115) 1 0.235 91.1 0.005 105 (0.0201, n = 5)(1.77, n = 5) 2 0.642 95.9 0.00882 96.1 (0.0294, n = 2) (0.553, n = 2)(0.00269, n = 2) (0.742, n = 2) 3 0.421 95.4 (0.181, n = 2) (2.20, n =2) 4 0.245 86.9 0.00480 92.4 (0.0638, n = 3) (5.93, n = 3) (0.000138, n= 2) (14.0, n = 2) 5 0.196 91.3 (0.0375, n = 3) (6.90, n = 3) 266 0.86563.4 0.016 17.1 (0.328, n = 2) (1.31, n = 2) 267 0.867 62.3 0.00901 16.5272 0.651 66.5 >12.0 ND (0.0427, n = 2) (0.741, n = 2) 298 1.03 57.3 3000.405 85.6 0.0054 38.4 301 0.435 91.4 0.00267 93.7 (0.0848, n = 3)(3.63, n = 3) 302 0.268 98.6 0.00219 98.4 303 0.547 74.3 0.0179 47.7(0.0998, n = 2) (2.99, n = 2) 304 0.561 77.1 305 0.389 76.3 306 0.37876.1 315 0.601 44.2 0.0199 25.4 316 0.766 56.7 0.00608 26.1 (0.0469, n =2) (3.14, n = 2) 317 0.536 53.7 318 0.415 58.4 288 0.666 66.7 0.0067421.3 (0.104, n = 3) (4.09, n = 3) (0.00278, n = 3) (1.94, n = 3) 3190.657 65.7 323 0.79 81.9 324 0.475 84.5 289 0.404 83.7 0.0124 51.3(0.0247, n = 3) (3.81, n = 3) (0.00151, n = 3) (6.05, n = 3) 325 0.41497.9 326 0.663 61.6 327 0.287 75.6 0.00379 41.6 328 0.481 66.3 329 0.34383.6 0.00473 63.4 330 1.05 47.8 >10.9 ND (0.275, n = 2) (1.16, n = 2)331 0.375 80.9 0.0128 44.3 (0.0274, n = 4) (2.54, n = 4) 332 0.453 81.50.0171 45.6 (0.0479, n = 4) (4.65, n = 4) 333 0.442 83.4 0.0548 58.2(0.00535, n = 2) (0.439, n = 2) 334 0.432 70.2 >10.3 ND 335 0.285 89.30.00531 73 336 0.377 90.2 0.00778 82.5 290 0.466 66.2 0.0238 20.0(0.0664, n = 9) (3.12, n = 9) (0.00530, n = 4) (1.15, n = 4) 337 0.32259.5 0.0174 34.1 338 0.0189 47 339 0.326 74.1 0.0107 44.0 (0.0357, n =3) (7.97, n = 3) (0.00238, n = 2) (2.40, n = 2) 340 0.450 67.4 0.010720.1 (0.0182, n = 5) (5.12, n = 5) (0.00711, n = 4) (2.31, n = 4) 3410.496 78.9 0.0188 21.9 342 0.414 77.2 0.035 20.7 343 0.522 74.9 0.045541.4 344 0.423 85.8 0.0343 46 345 0.684 62 0.00308 74.7 (0.000666, n =2) (2.86, n = 2) 346 0.737 56.6 0.00325 19.3 (0.201, n = 3) (3.94, n =3) (0.00105, n = 3) (0.767, n = 3) 347 0.759 46.9 0.00542 24.6 (0.00152,n = 2) (2.81, n = 2) 348 0.66 47.7 0.00346 19.8 (n = ½) 349 0.464 64.50.0151 18.4 (0.0290, n = 4) (1.68, n = 4) (0.00111, n = 2) (0.337, n =2) 350 0.589 64.1 0.0108 21.8 351 0.563 66.5 0.0196 23.5 352 0.552 63.50.00421 17.4 (0.0267, n = 2) (1.51, n = 2) (n = ½) 353 1.96 63.1 0.55923.0 (0.108, n = 2) (0.408, n = 2) 291 0.466 65.0 >10.0 ND (0.0476, n =6) (2.15, n = 6) (n = ¼) 354 0.967 53.3 0.255 22.7 (n = ½) 355 1.76 50.60.363 18.3 356 >10.5 ND 357 0.118 18.2 358 0.414 72.3 0.00938 21.4(0.00356, n = 2) (1.27, n = 2) (0.00413, n = 3) (2.47, n = 3) 359 0.49669.7 0.0841 28.4 360 0.0395 25.8 361 0.269 20.2 (n = ½) 362 >11.0 ND 3630.943 69.6 0.135 22.1 364 >12.0 ND 292 0.429 71.5 0.00774 29.0 (0.0190,n = 4) (3.33, n = 4) (0.00199, n = 4) (3.96, n = 4) 293 0.368 70.60.00719 29.5 (0.0304, n = 4) (0.715, n = 4) (0.00168, n = 4) (6.23, n =4) 365 0.464 66.9 0.00703 20.8 (0.0178, n = 3) (1.35, n = 3) (0.00233, n= 4) (1.78, n = 4) 366 0.409 67.6 0.00557 21.2 (0.0308, n = 3) (3.55, n= 3) (0.00363, n = 2) (0.163, n = 2) 367 0.289 89.7 0.00666 70.6(0.00118, n = 2) (8.61, n = 2) 368 0.495 68.9 0.0479 21.3 (0.0205, n =2) (4.03, n = 2) 369 0.381 58.8 0.0414 19.9 (n = ½) 370 0.428 63.70.00990 23.0 (0.00149, n = 2) (0.470, n = 2) 371 0.27 62.5 0.0142 21.7(0.00333, n = 2) (0.711, n = 2) 372 0.379 69.1 0.00981 32.9 (0.00630, n= 2) (1.65, n = 2) 373 0.336 65.6 0.00954 22.9 (0.00348, n = 2) (5.88, n= 2) 374 0.345 67.1 0.0218 34.7 375 0.419 70.4 0.0114 24.2 376 0.32672.6 0.0123 25.6 377 0.356 68.4 0.00532 16.7 378 0.359 68.6 >10.2 ND 3790.239 71 0.0181 31.9 380 0.188 66.8 0.0137 35 381 0.273 73.6 0.0155 25.8Comparator 0.442 62.9 >10.5 (n = ⅕) ND Tirzepatide (se = 0.0311, (se =1.28, n = 9( n = 9) hGLP1R B-Arrestin2 hGLP1R B- Rel EC50 uM (SEM,Arrestin2 % Top Example n) (SEM, n) 0.00274 104 (0.000359, n = 42)(3.45, n = 42) 1 0.005 105 2 0.00882 96.1 (0.00269, n = 2) (0.742, n =2) 3 4 0.00480 92.4 (0.000138, n = 2) (14.0, n = 2) 266 0.016 17.1 2670.00901 16.5 272 >12.0 ND 300 0.0054 38.4 301 0.00267 93.7 302 0.0021998.4 303 0.0179 47.7 315 0.0199 25.4 316 0.00608 26.1 288 0.00674 21.3(0.00278, n = 3) (1.94, n = 3) 289 0.0124 51.3 (0.00151, n = 3) (6.05, n= 3) 327 0.00379 41.6 329 0.00473 63.4 330 >10.9 ND 331 0.0128 44.3 3320.0171 45.6 333 0.0548 58.2 334 >10.3 ND 335 0.00531 73 336 0.00778 82.5290 0.0238 20.0 (0.00530, n = 4) (1.15, n = 4) 337 0.0174 34.1 3380.0189 47 339 0.0107 44.0 (0.00238, n = 2) (2.40, n = 2) 340 0.0107 20.1(0.00711, n = 4) (2.31, n = 4) 341 0.0188 21.9 342 0.035 20.7 343 0.045541.4 344 0.0343 46 345 0.00308 74.7 (0.000666, n = 2) (2.86, n = 2) 3460.00325 19.3 (0.00105, n = 3) (0.767, n = 3) 347 0.00542 24.6 (0.00152,n = 2) (2.81, n = 2) 348 0.00346 19.8 (n = ½) 349 0.0151 18.4 (0.00111,n = 2) (0.337, n = 2) 350 0.0108 21.8 351 0.0196 23.5 352 0.00421 17.4(n = ½) 353 0.559 23.0 (0.108, n = 2) (0.408, n = 2) 291 >10.0 ND (n =¼) 354 0.255 22.7 (n = ½) 355 0.363 18.3 356 >10.5 ND 357 0.118 18.2 3580.00938 21.4 (0.00413, n = 3) (2.47, n = 3) 359 0.0841 28.4 360 0.039525.8 361 0.269 20.2 (n = ½) 362 >11.0 ND 363 0.135 22.1 364 >12.0 ND 2920.00774 29.0 (0.00199, n = 4) (3.96, n = 4) 293 0.00719 29.5 (0.00168, n= 4) (6.23, n = 4) 365 0.00703 20.8 (0.00233, n = 4) (1.78, n = 4) 3660.00557 21.2 (0.00363, n = 2) (0.163, n = 2) 367 0.00666 70.6 (0.00118,n = 2) (8.61, n = 2) 368 0.0479 21.3 (0.0205, n = 2) (4.03, n = 2) 3690.0414 19.9 (n = ½) 370 0.00990 23.0 (0.00149, n = 2) (0.470, n = 2) 3710.0142 21.7 (0.00333, n = 2) (0.711, n = 2) 372 0.00981 32.9 (0.00630, n= 2) (1.65, n = 2) 373 0.00954 22.9 (0.00348, n = 2) (5.88, n = 2) 3740.0218 34.7 375 0.0114 24.2 376 0.0123 25.6 377 0.00532 16.7 378 >10.2ND 379 0.0181 31.9 380 0.0137 35 381 0.0155 25.8Composition for Oral Administration

A peptide is dissolved in Tris buffer (pH 8.0, 50 mM). A Permeationenhancer (“PE”) is prepared as follows: C10 is dissolved in Tris buffer(pH 8.0, 50 mM), LC, DPC, C12-maltoside and Rhamnolipid are eachdissolved in phosphate buffered saline (“PBS”) (1×, pH 7.2). A solutionof peptide, a PE, and a protease inhibitor is mixed to reach a finalpeptide concentration of 300 uM, PE at 100 mM (5% w/v for Rhamnolipid)and 1% (v/v) for the protease inhibitor.

A peptide is incubated at 37° C. in 1% (v/v) rat small intestinal fluidor 50% (v/v) pig small intestinal fluid with and without a peptidaseinhibitor. At different time points, samples are taken out, followed byquenching with 1% TFA in 50% ACN/water to stop the enzyme activity. Theintact peptide at different time points is analyzed by high-performanceliquid chromatography (HPLC) equipped with an ultraviolet (UV) detectoror LC-MS/MS and normalized to the amount of peptide before mixing withthe enzyme solution. A study using a peptide of Example 2 and a peptideof Example 4 are reported in Table 15.

TABLE 15 % peptide intact Recombinant protease inhibitor Small(concentration) intestinal fluid 0 min 15 min 30 min 60 min rSBTI (5mg/mL) + Peptide (Example 4) 50% v/v pig 100.00 96.96 96.28 88.57Peptide Example 4 (no PI; control) 50% v/v pig 100.00 72.52 41.44 18.98rSBTI (5 mg/mL) + Peptide Example 2 50% v/v pig 100.00 103.02 112.6987.33 Peptide Example 2 (no PI; control) 50% v/v pig 100.00 2.42 1.903.09 rSBTCI (0.5 mg/mL) + Peptide Example 2 50% v/v pig 100.00 131.71126.53 123.70Table 15 results support that an oral formulation composition for apeptide of Example 4 may be prepared using a PE and no PI.Oral Formulation Composition

Examples of formulation compositions for a peptide of this invention areprovided by Table 16. The formulation compositions for peptides of thisinvention are in no way limited by the examples provided.

TABLE 16 Formulation Formulation composition Concentration 1 Peptide(Example 1; or Example 4 2.4 mg/mL or Example 3) C10 250 mM SBTI 75mg/mL 2 Peptide (Example 1) 2.4 mg/mL LC 500 mM Citric acid 500 mM 3Peptide (Example 1) 2.4 mg/mL NaTDC 250 mM SBTI 75 mg/mL 4 Peptide(Example 1, Example 2, 2.4 mg/mL or Example 4) C10 250 mM SBTI 12 mg/mL5 Peptide (Example 1 or Example 2) 2.4 mg/mL C10 125 mM SBTI 12 mg/mL 6Peptide (Example 1) 2.4 mg/mL C10 125 mM SBTI 24 mg/mL 7 Peptide(Example 4) 2.4 mg/mL C10 250 mM SFTI 12 mg/mLThe effect of formulation composition on a peptide exposure is evaluatedin rats via intrajejunal (IJ) administration using liquid formulations.To prepare liquid formulations for a rat IJ administration, a peptide,C10 or NaTDC and SBTI is dissolved in 50 mM Tris buffer pH 8.0 and mixedto achieve final desired concentration. For LC/citric acid formulation,LC and citric acid are dissolved in water and mixed with a peptidedissolved in Tris buffer. Formulation compositions provided in Table 16may be administered as an oral composition.Enteric Capsules

An enteric capsule composition may be desired for certain peptides ofthis invention and may be prepared using methods for example, as setforth by Table 17. Enteric compositions may be prepared by blendingingredients together and filling the blend in enteric capsules.

An enteric composition of Table 17 is prepared adding half of the statedamount of sodium decanoate to a mortar. SBTI (for Examples 382-385) orSFTI (for Examples 386 and 387), and a peptide (peptides of Examples1-4), as shown in Table 17. A remaining half of the sodium decanoate isadded. A mixture is gently blended together using pestle, and spatula.If desired, additional mixing using pestle provides a homogenous blend.A capsule may be manually filled by individually weighing the requiredamount of blend, filling in capsules, and securely closing the capsulecaps to the capsule bodies.

Dissolution testing of a single capsule is completed using knownmethods. A peptide of this invention may be formulated as an entric oralcomposition.

TABLE 17 Composition of Individual Enteric Capsule for FormulationEnteric Enteric Enteric Enteric Enteric Enteric Peptide Example ExampleExample Example Example Example Component 382 383 384 385 386 387Example 2 12.50 12.50 Example 4 12.50 12.50 Example 1 12.50 Example 312.50 Sodium 250.00 250.00 250.00 250.00 250.00 250.00 decanoate (C10)SBTI 62.50 62.50 62.50 62.50 SFTI 62.50 62.50 Total Capsule 325.00325.00 325.00 325.00 325.00 325.00 Fill Weight Capsule Size Size 00 Size00 Size 00 Size 00 Size 00 Size 00Amino Acid Sequences

GIP (Human) SEQ ID NO: 1 YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQGLP-1 (7-36) (Human) SEQ ID NO: 2 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂SEQ ID NO: 3 R₁X₁X₂X₃GTX₆TSDX₁₀X₁₁X₁₂X₁₃X₁₄DX₁₆X₁₇AX₁₉X₂₀X₂₁X₂₂X₂₃X₂₄X₂₅X₂₆X₂₇X₂₈X₂₉X₃₀X₃₁ SEQ ID NO: 4 PX₃₂X₃₃X₃₄-R₂ SEQ ID NO: 5PX₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₈X₃₉-R₂ SEQ ID NO: 6PX₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₈X₃₉X₄₀-R₂ SEQ ID NO: 7K[(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)_(q)-CO₂H]X₃₂X₃₃X₃₄-R₂ SEQ ID NO: 8K[(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)_(q)-CO₂H]X₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₈X₃₉-R₂ SEQ ID NO: 9K[(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)_(q)-CO₂H]X₃₂X₃₃X₃₄X₃₅X₃₆X₃₇X₃₈X₃₉X₄₀-R₂

Example 1

SEQ ID NO: 10 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂

Example 2

SEQ ID NO: 11 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂

Example 3

SEQ ID NO: 12 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₈-CO₂H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH₂

Example 4

SEQ ID NO: 13 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH₂

Example 5

SEQ ID NO: 14 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH₂)₁₆-CO₂H)AQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH₂ SEQ ID NO: 297PSSG-R₂ SEQ ID NO: 298 PSSGAPPPS-R₂ SEQ ID NO: 299 PSSG SEQ ID NO: 300PSSG-NH₂ SEQ ID NO: 301 PSSGAPPPS SEQ ID NO: 302 PSSGAPPPS-NH₂Legal Framework

The material in ASCII text file named “X21852 Sequence Listing”, createdon 09/19/2019 and of the size 440 KB, is hereby incorporated byreference.

We claim:
 1. A compound wherein the compound is any one of the aminoacid sequences selected from the group consisting of SEQ ID NO:10, SEQID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14, or apharmaceutically acceptable salt thereof.
 2. A compound as claimed byclaim 1 wherein the compound is SEQ ID NO:13, or a pharmaceuticallyacceptable salt thereof.
 3. A compound as claimed by claim 1 wherein thecompound is SEQ ID NO:10, or a pharmaceutically acceptable salt thereof.4. A compound as claimed by claim 1 wherein the compound is SEQ IDNO:11, or a pharmaceutically acceptable salt thereof.
 5. A compound asclaimed by claim 1 wherein the compound is SEQ ID NO:12, or apharmaceutically acceptable salt thereof.
 6. A compound as claimed byclaim 1 wherein the compound is SEQ ID NO:14, or a pharmaceuticallyacceptable salt thereof.
 7. A pharmaceutical composition comprising anyone of the compounds as claimed by claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier, diluent, or excipient.
 8. A method of treating type 2 diabetesmellitus or obesity comprising; administering an effective amount of anyone of the compounds as claimed by claim 1, or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.
 9. A method oftreating type 2 diabetes or obesity comprising administering aneffective amount of a compound of the amino acid sequence SEQ ID NO:13,or a pharmaceutically acceptable salt thereof, to a patient in needthereof.
 10. A method of providing therapeutic weight loss, comprisingadministering an effective amount of any one of the compounds as claimedby claim 1, or a pharmaceutically acceptable salt thereof, to a subjectin need thereof.